Flexible Synthesis of Phosphoryl-Substituted Imidazolines, Tetrahydropyrimidines, and Thioamides by Sulfur-Mediated Processes

Article abstract of DOI:10.1021/acs.joc.9b01384

The solvent-free sulfur-mediated reactions of phosphinic chlorides with alkyl diamines were developed for the practical synthesis of unknown phosphoryl-substituted 4,5-dihydro-1H-imidazoles, 1,4,5,6-tetrahydropyrimidines, and thioamides. Their good tolera

Full text of DOI:10.1021/acs.joc.9b01384

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Article
Flexible Synthesis of Phosphoryl-Substituted Imidazolines,
Tetrahydropyrimidines and Thioamides by Sulfur-Mediated Processes
Mikhail Kozlov, Alexander Komkov, Timofey Losev, Alexey Tyurin,
Andrey S. Dmitrenok, Igor Zavarzin, and Yulia Alexeevna Volkova
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01384 • Publication Date (Web): 08 Aug 2019
Downloaded from pubs.acs.org on August 9, 2019
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The Journal of Organic Chemistry
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Flexible
Synthesis
of
Phosphoryl-Substituted
Imidazolines,
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5
6
Tetrahydropyrimidines and Thioamides by Sulfur-Mediated Processes
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Mikhail Kozlov, Alexander Komkov, Timofey Losev, Alexey Tyurin, Andrey Dmitrenok, Igor
Zavarzin, Yulia Volkova*
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N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp.,
119991 Moscow, Russia, yavolkova@gmail.com
R3
R3
N
R1
R2
R1
R2
O
O
O
R1
R2
H
N
n = 1
n = 2
P
P
N
P
=
Cl
H2N
R3
S8
+
+
neat
-H2S
neat
-H2S
n
n
N
N
R1, R2 = HNAlk, NHAr,
NAlk2
4
-
=
2
,
10 examples
32-70%
2
7 examples
44-83%
0
-
6
H2 O
n
t
a
R3 = Alk, Ar
e
R 3
O
n
=
H
S
O
R1
P
R2
H
R2
H
R1
N
R3
R1 P
R2
N
N
N
P
n
n
H
H
S
S
O
4 examples
15-68%
7 examples
19-87%
ABSTRACT: The solvent-free sulfur-mediated reactions of phosphinic chlorides with alkyl
diamines were developed for the practical synthesis of unknown phosphoryl-substituted 4,5-
dihydro-1H-imidazoles, 1,4,5,6-tetrahydropyrimidines and thioamides. Their good tolerance to
functional groups, broad substrate scope and easy scalability were shown. The chemoselective
preparation of a variety of phosphoryl-substituted bis(thioamides) was accomplished via the
adjustment of a solvent.
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Introduction
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Organophosphorus compounds are of great interest due to their wide occurrence in numerous
natural products, various biologically active compounds, fine chemicals, metal ligands and
materials.1 In particular, imidazolines, tetrahydropyrimidines and thioamides with phosphoryl
substituents are lead compounds for neuroprotective,2 anti-inflammatory3 and anticancer4 agents
(Figure 1). Phosphoryl-substituted imidazolines are used in the design of N-heterocyclic
carbenes (NHC) complexes.5 Tetrahydropyrimidines bearing a phosphoryl group are highly
promising ligands for transition metal complexes.6 Phosphoryl thioamides have found broad
application as ligands for metal cations,7 polymerization initiators,8 hybrid materials building
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blocks and multifunctional reagents.10 In recent years organophosphorus compounds have
gained significant attention in organic synthesis, but convenient and valuable synthetic
approaches for their preparation are still required.11 Masson et al. reported the synthesis of 2-
phosphoryl-substituted
imidazoline
derivatives
by
cyclocondensation
of
phosphonodithioformates with diamines.12 To the best of our knowledge, 2-phosphoryl-
substituted tetrahydropyrimidines have not been reported previously. Synthetic approaches to
phosphoryl thioamides via Pudovik-type13 and Arbuzov-type reactions14 are based on
commercially unavailable, toxic and foul-smelling reagents. Hence, a facile flexible synthetic
method particularly suitable for the preparation of a diversity of organophosphorus derivatives
still needs to be developed.
(R2N)2OP
N
Ph
N
O
R
R
S
OH
P
N
N
R
R
H2N
N
N
(EtO)2OP
H
N
O
Ph
R
I2 receptors ligands
neuroprotective agents
aminopeptidase inhibitor
anticancer agents
anti-inflammatory
agents
Figure 1. Biologically active organophosphorus compounds.
At the same time, sulfur mediated organic reactions are advantageous because of capacity to
provide a range of structurally diverse products with good functional group tolerance.15 A series
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of reports published in the last decade demonstrate the utility of elemental sulfur in reactions
with amines for the synthesis of imidazoles,16 benzo[d]imidazoles,17 imidazo[1,5-a]pyridines18
and pyrazoles.19 Recently, our group has disclosed the Willgerodt-type20 reaction of phosphinic
chlorides with sulfur and amines as a highly efficient approach to phosphoryl thioamides
(Scheme 1a).21 Herein, we propose that using alkyl diamines in the reaction with phosphinic
chlorides and sulfur is an efficient tool for the construction of 2-phosphoryl-substituted 2-
imidazolines and 1,4,5,6-tetrahydropyrimidines (Scheme 1b). Additionally, we discovered the
switching of the reaction pathway to bis(thioamides) mediated by solvent effects.
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Scheme 1. Sulfur-mediated reaction of phosphinic chlorides with amines in the synthesis of
phosphoryl thioamides and phosphoryl-substituted N-heterocycles.
a) Previous work:
R3
O
O
R1
R2
R1
H2O or DMF
-HCl
R3
P
N
P
Cl
+
S8
R4
+
NH
R4
R2
R1, R2
=
S
HNAlk, NHAr,
NAlk2, Ar
R5
N
R1
O
b) This work:
O
R1
P
H
N
neat
n = 0,1
-H2S
NH2
R2
P
n
R2
n
n = 0-5
N
S
R3
O
R1
S8
n
H2N
NH2
+
+
P
Cl
R3
-HCl
R2
O
O
H2O
R1
H
N
R2
R1, R2 = HNAlk, NHAr, NAlk2, Ar; R3 = Alk
H
N
P
P
n = 0-5
R2
R1
n
S
S
Results and Discussion
Initially, we studied the reaction of phosphinic chlorides 1 with 1,2-ethylenediamine derivatives
2 in the presence of sulfur (Table 1). A brief optimization identified mild conditions providing a
reliable route to desired substituted imidazolines 3 (see Supporting Information). We were
pleased to find that heating of mixtures of compounds 1a–f with sulfur in ethylenediamine
derivatives 2a–c to 40–85 °C resulted in the formation of desired imidazolines 3a–j in 32–70%
yields. We also tested N,N-dimethylformamide, 1,4-dioxane and water as solvents. However the
reactions were found to be fully inefficient.
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Table 1. Synthesis of imidazolines 3a,b
R4
O
P
R1
R3
S8
O
R1
N
R3
P
Cl
+
R2
H2N
NHR4
40 or 85 o
C
N
R2
5
neat, 7 h
6
1a-e
2a-c
3a-j
7
8
9
O
O
O
O
PhHN
PhHN
RHN
RHN
N
P
P
P
N
N
N
N
10
11
12
13
14
15
16
17
18
19
20
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60
HN
HN
HN
O
3b
A
)
B
)
3a
, 44% (
A
, R = Bu, 65% (
)
3d
A
)
, 68% (
scale-up 1.6 g
t
3c
, R = Bu, 43% (
Me
N
O
O
O
PhHN
PhHN
BuHN
H
H
Ph
P
P
P
N
N
N
Et2N
BuHN
N
HN
N
3f
A
)
, 32% (
3g
A
)
, 70% (
3e
B
)
, 64% (
O
O
O
H
O
P
N
BuHN
BuHN
O
N
P
N
N
P
N
N
N
N
N
N
O
O
3h
A
)
, 55% (
3i
A
)
, 48% (
3j
A
)
, 47% (
a
Reaction conditions: sulfur (0.22 g, 7.0 mmol), phosphinic
chloride 1 (1.4 mmol), diamine 2 (20 mmol) at 40 oC (A) or 85 oC
(B) over 7 h. b Yields after column chromatography.
A variety of substituents at phosphorus were tolerated, and the use of ethylenediamine 2a
afforded compounds 3a–e bearing symmetrical and asymmetrical phosphonic acid diamide
substituents. Moreover, the reaction with 2-methyl-substituted ethylenediamine 2b gave 5-
methyl-4,5-dihydroimidazoles 3f–h in 32–70% yields. N-methylethylenediamine 2c successfully
reacted with phosphinic chlorides 1b,c to afford N-substituted imidazolines 3i and 3j in 48% and
47%, respectively. It’s important to stress, that (chloromethyl)phosphonates, represented by
formula (RO)2POCH2Cl (R = OPh, OEt), under the optimized conditions did not give target
imidazolines due to side processes of transamidation at the phosphinic center.
To explore the efficiency of this method, a gram-scale experiment was conducted. The proposed
method can easily be scaled-up without loss in yield. Thus, the treatment of
(chloromethyl)phosphonic acid bis(morpholide) 1d (2.0 g, 7.0 mmol) with ethylenediamine 2a
(6.5 mL, 98 mmol, 14 equiv) and sulfur on heating to 40 °C for 7 h gave imidazoline 3d in 79%
yield (1.6 g).
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Moreover, the transformation was extended to the 1,3-propylenediamine (2d) (Table 2). Diverse
phosphinic chlorides 1a–e bearing aniline substituents, n-butylamine, tert-butylamine,
morpholine and diethylamine substituents were well tolerated under the reaction conditions to
give the tetrahydropyrimidines 4a–e in 44% to 83% yields. Starting from
(chloromethyl)phosphonic acid N-methyl-N-phenylazepane amide (2g), product 4f bearing an
asymmetric phosphonic acid diamide moiety was obtained in 68% yield. Besides,
2,2-dimethylpropane-1,3-diamine (2e) can also be employed to prepare 3,3-dimethyl-substituted
tetrahydropyrimidine 4g in 57% yield (Table 2).
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Table 2. Synthesis of tetrahydropyrimidines 4a,b
R1
O
H
S8
O
R1
R2
P
N
R2
H2N
NH2
+
P
Cl
R3 R3
R3
R3
40 or 85 o
C
N
neat, 7 h
1a-g
2d,e
4a-f
O
O
O
P
O
RHN
PhHN
PhHN
N
H
H
H
P
P
N
N
N
RHN
N
N
N
N
O
4a
, 83% (
A
4b A
, R = n-Bu, 44% ( )
)
4d
, 68% (
A
)
4c
B
, R = tert-Bu, 78% (
)
O
Me
O
P
O
O
H
Et2N
Et2N
N
H
H
N
P
P
N
Ph
N
N
N
N
N
N
N
O
4e
, 65% (
B
4f
B
4g A
, 57% ( )
)
, 68% (
)
a
Reaction conditions: sulfur (0.22 g, 7.0 mmol), phosphinic
chloride 1 (1.4 mmol), diamine 2 (20 mmol) at 40 oC (A) or 85
oC (B) over 7 h. b Yields after column chromatography.
The subsequent elongation of diamine 2 alkyl chains, as well as the installation of electron-
withdrawing substituents decreasing NH-group reactivity, resulted in the formation of linear
products — phosphoryl thioamides 5 (Table 3). The reaction of (5-nitropyridin-2-yl)ethane-1,2-
diamine (2f) with phosphinic chloride 1d afforded product 5a in 15% yield. 1,4-Butanediamine
(2g), 1,5-pentanediamine (2h) and 1,6-hexanediamine (2i) reacted smoothly to form thioamides
5b-d in 68%, 49% and 68% yields, respectively.
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Table 3. Synthesis of phosphoryl thioamides 5a,b
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7
8
9
O
O
N
N
P
Cl
O
1d
O
H
N
O
S8
P
N
+
NHR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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n
N
40 o
C
S
5a-d
NHR
2f-i
neat, 7 h
n
H2N
O
O
O
NO2
O
O
H
N
N
H
N
P
P
N
N
N
NH2
N
N
H
S
S
O
O
c
5b
, 68%
5a
, 15%
O
O
O
N
H
O
H
P
N
N
NH2
P
N
N
NH2
N
S
S
O
O
5c
, 49%
5d
, 68%
a
Reaction conditions: sulfur (0.22 g, 7.0 mmol), phosphinic
chloride 1d (375 mg,1.4 mmol), diamine 2 (20 mmol), at 40 oC
over 7 h. b Yields after column chromatography. с The reaction
was performed with Et3N in DMF at 45 oC over 5 h.
Surprisingly, it was found that in the presence of water reaction of phosphinic chlorides 1 with
diamines 2 and elemental sulfur was accompanied by formation of bis(thioamides) 6 (Table 4).
We assumed that water-organic two-phase system as media can provides a coacervate phase that
is rich in phosphinic chloride 1 and diamine 2 aqueous-rich phase, hereby promotes
bisthiophosphorylation of amine. Optimization of reaction conditions indicated that the
maximum yields of compounds 6 were achieved at 1:1 ration of phosphinic chlorides 1 and
diamines 2. The principal result is the formation of bis(thioamides) 6 as the major products in all
cases irrespective of the diamine alkyl chain length. Thus, various diamines with a C3–C8 alkyl
chain reacted smoothly with (chloromethyl)phosphonic acid bisdiethyl amide (2f) to form
compounds 6a–g in 19–87% yields. Low yields of products 6b,c are attributed to numerous side
processes giving complex mixtures of products.
Table 4. Synthesis of bis(thioamides) 6a,b
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3
O
Et2N
Et2N
P
Cl
4
5
6
7
1f
O
R
R
O
P
H
N
H
Et2N
NEt2
S8, DIPEA
P
N
+
n
H2O, , 5h
Et2N
NEt2
R
R
S
S
6a-g
H2N
NH2
n
8
2d,e,g-k
9
O
O
P
O
O
P
H
N
H
H
N
H
Et2N
NEt2
Et2N
NEt2
10
11
12
13
14
15
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P
N
P
N
Et2N
NEt2
S
Et2N
NEt2
S
S
S
6a
, 58%
6b
6d
, 19%
S
O
P
O
O
P
H
H
H
NEt2
Et2N
NEt2
Et2N
N
P
N
N
P
N
NEt2
Et2N
NEt2
Et2N
H
O
S
S
S
6c
, 40%
S
, 62%
O
P
6e
6f
6g
, m = 1, 79%
, m = 2, 71%
, m = 3, 87%
H
NEt2
NEt2
Et2N
N
P
N
n
Et2N
H
O
S
a Reaction conditions: sulfur (41 mg, 1.29 mmol), phosphinic
chloride 1f (100 mg, 0.43 mmol), diamine 2 (0.43 mmol), and
DIPEA (224 µL, 1.29 mmol) in water (1 mL) under reflux over
5 h. b Yields after column chromatography.
The possible mechanism for the condensation of phosphinic chlorides with sulfur and alkyl
diamines suggested by literature precedents15,20 is shown in Scheme 2. The reaction is initiated
by the nucleophilic ring opening of S8 by amine I, leading to polysulfide II. Polysulfide II is
highly nucleophilic and adds to the chloromethyl reaction center of phosphinic chloride III to
provide polysulfide IV. The cleavage of intermediate IV S–S bond with amine along with proton
abstraction results in thioaldehyde V. Following imination of the former gives VI, which
undergoes addition with polysulfides II. Finally the elimination of polysulfide II’ from
intermediate VII affords thioamide VIII. The intramolecular ring closure of thioamides VIII
with short alkyl chains (m = 1, 2) followed by hydrogen sulfide elimination provides cyclic
products XIX. In water, compounds VIII with a terminal NH2 group undergo subsequent
thiophosphorylation to form bis(thioamides).
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Scheme 2. Plausible mechanism.
4
5
6
7
8
9
O
S8
R
P
Cl
H
NH2
m
RHN
N
S
R
RHN
m
S
n S-
III
I
, m = 1-7
II
, n = 0-6
S
-S
S
O
R
RHN
P
S
S
n
NHR
N
H
nS-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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52
53
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58
59
60
S
N
m
R
H
II'
IV
O
O
R
R
P
S
S
NHR
P
S
S
N
n
m
R
H
R
N
H
V
VII
m
NHR
I
O
R
P
N
NHR
m
R
H
VI
II
O
R
S
P
O
R
R
m = 1,2
-H2S
NHR
m
R
N
P
N
H
N
R
m
VIII
XIX
In conclusion, we demonstrated the utility of the sulfur-mediated reaction of phosphinic
chlorides with alkyl diamines for the easy access to a variety of phosphoryl-substituted products.
A variety of 2-imidazoline, 1,4,5,6,-tetrahydropyrimidine and thioamide structures could be
prepared from readily available materials under solvent-free conditions or in water. The new
strategy significantly broadens the synthetic scope of organophosphorus compounds. Due to
operational simplicity, these protocols may be useful in pharmacological research and the design
of materials and ligands in metal complex catalysis.
■ EXPERIMENTAL SECTION
NMR spectra were acquired on Bruker Avance 600 and 300 spectrometers at room temperature;
the chemical shifts δ were measured in ppm relative to the solvent (1Н: CDCl3, δ = 7.27 ppm,
DMSO-d6, δ = 2.50 ppm; 13C: CDCl3, δ = 77.00 ppm, DMSO-d6, δ = 39.50 ppm). Splitting
patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, double
doublet; ddd, double double doublet. The coupling constants (J) are in Hertz. High-resolution
and accurate mass spectra were obtained on BrukermicrOTOF-QTM ESI-TOF (Electrospray
Ionization/Time of Flight) and Thermo Scientific* LTQ Orbitrap mass spectrometers. Mass
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spectra were recorded on a Finnigan Mat INCOS 50 Quadrupole Mass Spectrometer. Melting
points (mp) are uncorrected and were measured on a Boetius capillary melting point apparatus.
Analytical thin layer chromatography (TLC) was carried out on silica gel plates (silica gel 60
F254 aluminum supported plates); the visualization was accomplished with an UV lamp (365
nm) and using chemical staining with [KMnO4/H2SO4]. Column chromatography was performed
on silica gel 60 (230-400 mesh, Merck). Sulfur and all amines were commercially available and
were used without additional purification. All reactions were carried out using freshly distilled
and dry solvents. Phosphinic chlorides are readily available from chloromethylphosphonic
dichloride by simple treatment with amines, alcohols and Grignard reagents.22-24
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Chloromethylphosphonic acid bisphenyl amide (1a) was obtained according to literature
o
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protocol.22 Pale yellow solid, m.p. 98 – 100 C (m.p.lit 97 - 125 C).22 1H NMR (300 MHz,
DMSO-d6): δ 7.94 (d, JH-P = 11.3 Hz, 2H, 2 × NH), 7.26 – 7.12 (m, 8H, 4 × CH + 4 × CH), 6.98
– 6.80 (m, 2H, 2 × CH), 3.88 (d, JH-P = 8.0 Hz, 2H, CH2Cl). 31P NMR (121 MHz, DMSO-d6): δ
10.74. MS (ESI) 280 [M]+.
Chloromethylphosphonic acid bisbutyl amide (1b)21 was obtained according to literature
protocol.23 Pale yellow solid, m.p. 39 - 41 oC. 1H NMR (300 MHz, DMSO-d6): δ 4.22 (dt, JH-P
=
11.5 Hz, JH-H = 6.6 Hz, 2H, 2 × NH), 3.50 (d, JH-P = 8.3 Hz, 2H, CH2Cl), 2.86 – 2.67 (m, 4H, 2 ×
CH2), 1.46 – 1.34 (m, 4H, 2 × CH2), 1.33 – 1.20 (m, 4H, 2 × CH2), 0.86 (t, J = 7.1 Hz, 6H, 2 ×
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CH3). C{1H} NMR (75 MHz, DMSO-d6): δ 39.9 (CH2), 37.4 (d, JC-P = 118.4 Hz, CH2Cl),
34.4 (d, 3JC-P = 5.4 Hz, CH2), 19.9 (CH2), 14.2 (CH3). 31P NMR (121 MHz, CDCl3): δ 22.19.
Chloromethylphosphonic acid bis(tert-butyl) amide (1c)21 was obtained according to literature
protocol.23 Pale yellow solid, m.p. 96 – 98 oC. 1H NMR (300 MHz, CDCl3): δ 3.46 (d, JH-P = 9.0
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Hz, 2H, CH2Cl), 2.90 (br. s, 2H, 2 × NH), 1.35 (s, 18H, 6 × CH3). C{1H} NMR (75 MHz,
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CDCl3): δ 51.4 (d, JC-P = 40.6 Hz, 2 x C), 39.6 (d, JC-P = 117.9 Hz, CH2Cl), 31.80 (d, JC-P
=
4.1 Hz, 6 x CH3). 31P NMR (121 MHz, CDCl3): δ 17.27.
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Chloromethylphosphonic acid bismorpholine amide (1d)21 was obtained according to literature
protocol.23 Pale yellow solid, m.p. 103 - 105 oC (m.p.lit 89-91 oC). 1H NMR (300 MHz, CDCl3):
δ 3.80 – 3.57 (m, 10H, 4 × CH2 + CH2), 3.29 – 3.12 (m, 8H, 2 × CH2). 13C{1H} NMR (75 MHz,
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CDCl3): δ 67.1 (d, JC-P = 5.1 Hz, 4 × CH2), 44.5 (4 × CH2), 34.4 (d, JC-P = 123.7 Hz, CH2Cl).
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31P NMR (121 MHz, CDCl3): δ 23.79.
Chloromethylphosphonic acid N-methyl-N-phenyl ethyl amide (1e)21 was obtained according to
literature protocol.22 Pale yellow solid, m.p. 58 – 60 C H NMR (300 MHz, CDCl3): δ 7.41 –
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7.29 (m, 4H, Ph), 7.25 – 7.17 (m, 1H, Ph), 3.50 (d, JH-P = 7.9 Hz, 2H, CH2Cl), 3.34 – 3.02 (m,
7H, 2 × CH2 + CH3), 1.09 (t, J = 7.1 Hz, 6H, 2 × CH3). C{1H} NMR (75 MHz, CDCl3): δ
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144.6 (d, 2JC-P = 3.8 Hz, С), 129.4 (2 × CH), 126.7 (d, 3JC-P = 4.1 Hz, 2 × CH), 126.0 (CH), 39.0
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(d, JC-P = 3.9 Hz, 2 × CH2), 37.7 (d, JC-P = 3.5 Hz, CH3), 36.2 (d, JC-P = 127.0 Hz, CH2Cl),
13.8 (d, 3JC-P = 1.5 Hz, 2 × CH3). 31P NMR (121 MHz, CDCl3): δ 25.04.
Chloromethylphosphonic acid bisdiethyl amide (1f)21 was obtained according to literature
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protocol.23 Сolorless viscous liquid. H NMR (300 MHz, CDCl3): δ 3.62 (d, JH-P = 8.2 Hz, 2H,
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CH2Cl), 3.11-3.19 (m, 8H, 4 × CH2), 1.14 (t, J = 7.1 Hz, 12H, 4 × CH3). P NMR (121 MHz,
CDCl3): δ 27.98. MS (EI) 240 [M]+.
Chloromethylphosphonic acid N-methyl-N-phenyl azepaneamide (1g) was obtained according to
literature protocol.24 Whitre solid, m.p. 97 – 99 C. H NMR (300 MHz, CDCl3) δ 7.40 – 7.30
(m, 4H, Ph), 7.26 – 7.17 (m, 1H, Ph), 3.65 – 3.58 (m, 1H, CH2Cl), 3.58 – 3.51 (m, 1H, CH2Cl),
3.28 – 3.16 (m, 4H, CH2), 3.13 (d, JH-P = 9.1 Hz, 3H, CH3), 1.77 – 1.51 (m, 8H, 4 × CH2).
13C{1H} NMR (75 MHz, CDCl3): δ 144.8 (d, 2JC-P = 3.5 Hz, C), 129.3 (2 × CH), 126.3 (d, 3JC-P
= 4.1 Hz, 2 × CH), 125.8 (CH), 47.5 (d, 2JC-P = 3.2 Hz, 2 × CH2), 37.7 (d, 2JC-P = 3.6 Hz, CH3),
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35.8 (d, JC-P = 127.0 Hz, CH2Cl), 30.1 (d, JC-P = 4.4 Hz, 2 × CH2), 26.9 (2 × CH2). P NMR
(121 MHz, CDCl3): δ 24.74. HRMS (ESI) for C14H23ClN2OP ([M+H]+): calcd 301.1231, found
301.1238.
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General method for the synthesis of compounds 3,4, and 5. A mixture of diamine 2 (20
mmol, 14 equiv) and elemental sulfur (0.22 g, 7.0 mmol, 5 equiv) was stirred for 30 min at r.t.
Phosphinic chloride 1 (1.4 mmol, 1 equv) was added and resulting mixture was additionally
stirred for 7 h at 40 oC (procedure A) or at 85 oC (procedure B) in an oil bath until the complete
conversion of phosphinic chloride (TLC monitoring). The resulted mixture was cooled to r.t. and
viscous oil was extracted with CHCl3 (3 ×10 mL, for reactions with 1b-g) or MeOH (3 × 15 mL,
for reaction with 1a). Combined organic fraction was concentrated under reduced pressure and
product was isolated by column chromatography (eluent CHCl3 → CHCl3:MeOH, 60:1 for 3b-j,
4b-f, 5; CHCl3 : MeOH, 2:1 for 3a, 4a).
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(4,5-Dihydro-1H-imidazol-2-yl)di(phenylamino)phosphine oxide (3a). The general procedure A
was followed. Purification by column chromatography afforded product as pale yellow solid
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(186 mg, 44%), m.p. 218 - 219 C, Rf = 0.24 (CHCl3 : MeOH, 10:1). H NMR (300 MHz,
DMSO-d6): δ 3.59 (s, 4H, 2 × CH2), 6.85 – 6.87 (m, 2H, 2 × CH), 7.14 – 7.17 (m, 8H, 8 × CH),
8.32 (br. s, 2H, 2 × NH), signal of NH group was not observed. 13C{1H} NMR (75 MHz,
DMSO-d6): δ 49.5 (2 × CH2), 118.6 (d, 3JC-P = 7.0 Hz, 4 × CH), 121.5 (2 × CH), 129.3 (4 × CH),
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141.1 (2 × C), 164.0 (d, JC-P = 185.1 Hz, C). P NMR (121 MHz, DMSO-d6): δ -4.44. HRMS
(ESI) for C15H18N4OP ([M+H]+): calcd 301.1213, found 301.1203. IR (KBr): 3238, 2939, 2881,
1602, 1558, 1499, 1411, 1292, 1222, 1032, 948, 750, 691, 544, 503 cm-1.
(4,5-Dihydro-1H-imidazol-2-yl)di(n-butylamino)phosphine oxide (3b). The general procedure A
was followed. Purification by column chromatography afforded product as pale yellow solid
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(237 mg, 65%), m.p. 132 - 133 C, Rf = 0.21 (CHCl3 : MeOH, 10:1). H NMR (300 MHz,
DMSO-d6): δ 0.85 (t, JH-H = 8.0 Hz, 6H, 2 × CH3), 1.22 – 1.31 (m, 4H, 2 × CH2), 1.35 – 1.42 (m,
4H, 2 × CH2), 2.71 – 2.79 (m, 4H, 2 × CH2), 3.44 (s, 4H, 2 × CH2), 4.20 – 4.26 (m, 2H, 2 × NH),
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signal of NH group was not observed. C{1H} NMR (75 MHz, DMSO-d6): δ 14.2 (2 × CH3),
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19.9 (2 × CH2), 34.5 (d, JC-P = 5.0 Hz, 2 × CH2), 39.7 (d, JC-P = 8.0 Hz, 2 × CH2), 50.3 (2 ×
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CH2), 165.4 (d, 1JC-P = 181.1 Hz, C). 31P NMR (121 MHz, DMSO-d6): δ 8.45. HRMS (ESI) for
C11H26N4OP ([M+H]+): calcd 261.1839, found 261.1831. IR (KBr): 3268, 3070, 2957, 2929,
2861, 1568, 1467, 1378, 1291, 1192, 1119, 1098, 1039, 977, 952, 920, 869, 796, 677, 543 cm-1.
(4,5-Dihydro-1H-imidazol-2-yl)di(tert-butylamino)phosphine oxide (3c). The general procedure
B was followed. Purification by column chromatography afforded product as pale yellow solid
(156 mg, 43%), m.p. 225 - 227 oC, Rf = 0.32 (CHCl3 : MeOH, 5:1). 1H NMR (300 MHz, DMSO-
d6): δ 1.24 (s, 18H, 6 × CH3), 3.48 (s, 4H, 2 × CH2), 3.95 (d, JH-P = 8.0 Hz, 2H, 2 × NH).
13C{1H} NMR (75 MHz, DMSO-d6): δ 32.0 (d, 3JC-P = 4.0 Hz, 6 × CH3), 50.6 (2 × CH2), 51.1 (2
× C), 157.5 (d, 1JC-P = 196.4 Hz, C), signal of NH group was not observed. 31P NMR (121 MHz,
DMSO-d6): δ 2.30. HRMS (ESI) for C11H26N4OP ([M+H]+): calcd 261.1839, found 261.1846. IR
(KBr): 3425, 3229, 2971, 2871, 1570, 1552, 1475, 1390, 1365, 1286, 1249, 1224, 1210, 1184,
1020, 974, 949, 850, 564 cm-1.
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(4,5-Dihydro-1H-imidazol-2-yl)dimorpholinophosphine oxide (3d). The general procedure A was
followed. Purification by column chromatography afforded product as a pale yellow solid (275
mg, 68%), m.p. 144 - 145 oC, Rf = 0.33 (CHCl3 : MeOH, 10:1). 1H NMR (300 MHz, DMSO-d6):
δ 3.00 – 3.05 (m, 8H, 4 × CH2), 3.48 (s, 4H, 2 × CH2), 3.52 (t, JH-P = 4.0 Hz, 8H, 4 × CH2),
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signal of NH group was not observed. C{1H} NMR (75 MHz, DMSO-d6): δ 44.2 (4 × CH2),
50.3 (2 × CH2), 66.7 (d, 2JC-P = 5.0 Hz, 4 × CH2), 162.3 (d, 1JC-P = 187.2 Hz, C). 31P NMR (121
MHz, DMSO-d6): δ 12.20. HRMS (ESI) for C11H22N4O3P ([M+H]+): calcd 289.1424, found
289.1424. IR (KBr): 3171, 2971, 2886, 2853, 1573, 1443, 1368, 1286, 1256, 1224, 1195, 1114,
1092, 758, 967, 917, 849, 734, 706, 598, 536, 479 cm-1.
(Methylphenylamino)(diethylamino)(4,5-dihydro-1H-imidazol-2-yl)phosphi-ne oxide (3e). The
general procedure B was followed. Purification by column chromatography afforded product as
pale yellow oil (264 mg, 64%), Rf = 0.45 (CH2Cl2 : MeOH, 5:1). 1H NMR (300 MHz, CDCl3): δ
0.90 (t, JH-H = 7.1 Hz, 6H, 2 × CH3), 3.25 – 3.00 (m, 7H, 2 × CH2 + CH3), 3.71 (s, 4H, 2 × CH2),
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7.19 – 7.05 (m, 1H, CH), 7.33 – 7.22 (m, 2H, 2 × CH), 7.46 – 7.36 (m, 2H, 2 × CH), signal of
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NH group was not observed. C{1H} NMR (75 MHz, CDCl3): δ 13.3 (d, JC-P = 2.2 Hz, 2 ×
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CH3), 37.6 (d, 2JC-P = 6.1 Hz, CH3), 38.7 (d, 2JC-P = 4.5 Hz, 2 × CH2), 48.9 (d, 3JC-P = 7.3 Hz, 2 ×
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CH2), 125.6 (CH), 126.0 (d, JC-P = 4.4 Hz, 2 × CH), 129.0 (2 × CH), 143.7 (d, JC-P = 3.9 Hz,
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C), 164.0 (d, JC-P = 178.3 Hz, C). 31P NMR (121 MHz, CDCl3): δ 11.08. HRMS (ESI) for
C14H24N4OP ([M+H]+): calcd 295.1682, found 295.1691.
(5-Methyl-4,5-dihydro-1H-imidazol-2-yl)di(phenylamino)phosphine oxide (3f). The general
procedure A was followed. Purification by column chromatography afforded product as mixture
o
of tautomers, pale yellow solid (229 mg, 52%), m.p. 192 - 193 C, Rf = 0.25 (CHCl3 : MeOH,
10:1). 1H NMR (300 MHz, DMSO-d6): δ 1.06 (d, JH-H = 4.0 Hz, 3H, CH3), 3.18 (dd, JH-H = 8.0,
12.0 Hz, 1H, CH2), 3.72 (dd, JH-H = 12.0 Hz, 1H, CH2), 3.92 – 4.00 (m, 1H, CH), 6.80 – 6.88 (m,
2H, 2 × CH), 7.10 – 7.18 (m, 8H, 8 × CH), 8.04 (br. s, 2H, 2 × NH), signal of NH group was not
observed. C{1H} NMR (75 MHz, DMSO-d6): δ 21.7 (CH3), 56.5 (CH), 57.5 (CH2), 118.6 (d,
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3JC-P = 4.0 Hz, 4 × CH), 121.4 (2 × CH), 129.2 (4 × CH), 141.1 (2 × C), 162.3 (d, 1JC-P = 186.1
Hz, C). 31P NMR (121 MHz, DMSO-d6): δ -4.11. HRMS (ESI) for C16H20N4OP ([M+H]+): calcd
315.1369, found 315.1369. IR (KBr): 3232, 1602, 1552, 1499, 1410, 1283, 1226, 1032, 944,
749, 690, 546, 503 cm-1.
(5-Methyl-4,5-dihydro-1H-imidazol-2-yl)di(n-butylamino)phosphine oxide (3g). The general
procedure A was followed. Purification by column chromatography afforded product as mixture
o
of tautomers, pale yellow solid (270 mg, 70%), m.p. 91 - 92 C, Rf = 0.21 (CHCl3 : MeOH,
10:1). 1H NMR (300 MHz, DMSO-d6): δ 0.84 (t, JH-H = 8.0 Hz, 6H, 2 × CH3), 1.06 (d, JH-H = 4.0
Hz, 3H, CH3), 1.22 – 1.31 (m, 4H, 2 × CH2), 1.35 – 1.42 (m, 4H, 2 × CH2), 2.71 – 2.79 (m, 4H, 2
× CH2), 3.05 (dd, JH-H = 12.0 Hz, 1H, CH2), 3.60 (dd, J = 12.0 Hz, 1H, CH2), 3.78 – 3.87 (m, 1H,
CH), 4.21 – 4.29 (m, 2H, 2 × NH), signal of NH group was not observed. C{1H} NMR (75
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MHz, DMSO-d6): δ 14.2 (2 × CH3), 19.9 (2 × CH2), 22.0 (CH3), 34.1 (d, JC-P = 5.0 Hz, 2 ×
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CH2), 39.7 (2 × CH2), 56.9 (CH), 58.0 (CH2), 163.8 (d, JC-P = 180.1 Hz, C). P NMR (121
MHz, DMSO-d6): δ 8.26. HRMS (ESI) for C12H28N4OP ([M+H]+): calcd 275.1995, found
275.1993. IR (KBr): 3202, 2957, 2931, 2870, 1567, 1450, 1225, 1167, 1130, 1099, 967, 912,
732, 582 cm-1.
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(5-Methyl-4,5-dihydro-1H-imidazol-2-yl)dimorpholinophosphine oxide (3h). The general
procedure A was followed. Purification by column chromatography afforded product as mixture
o
of tautomers, as pale yellow solid (232 mg, 55%), m.p. 94 - 95 C, Rf = 0.47 (CHCl3 : MeOH,
10:1). 1H NMR (300 MHz, DMSO-d6): δ 1.08 (d, J = 6.0 Hz, 3H, CH3), 3.00 – 3.16 (m, 9H, 4 ×
CH2), 3.53 (t, JH-P = 5.0 Hz, 8H, 4 × CH2), 3.59 – 3.61 (m, 1H, CH2), 3.85 – 3.92 (m, 1H, CH),
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signal of NH group was not observed. C{1H} NMR (75 MHz, DMSO-d6): δ 21.9 (CH3), 44.2
(4 × CH2), 57.5 (CH2 + CH), 66.7 (d, 2JC-P = 5.0 Hz, 4 × CH2), 160.5 (d, 1JC-P = 187.2 Hz, C). 31P
NMR (121 MHz, DMSO-d6): δ 12.03. HRMS (ESI) for C12H24N4O3P ([M+H]+): calcd 303.1581,
found 303.1580. IR (KBr): 3259, 2963, 2917, 2854, 1568, 1453, 1371, 1299, 1259, 1226, 1188,
1138, 1112, 1090, 1022, 967, 916, 844, 733, 698, 610, 542, 477 cm-1.
(1-Methyl-4,5-dihydro-1H-imidazol-2-yl)di(n-butylamino)phosphine oxide (3i). The general
procedure A was followed. Purification by column chromatography afforded product as colorless
oil (185 mg, 48%), Rf = 0.12 (CHCl3 : MeOH, 10:1). 1H NMR (300 MHz, DMSO-d6): δ 0.86 (t,
JH-H = 8.0 Hz, 6H, 2 × CH3), 1.22 – 1.30 (m, 4H, 2 × CH2), 1.30 – 1.40 (m, 4H, 2 × CH2), 2.72 –
2.78 (m, 4H, 2 × CH2), 2.99 (s, 3H, CH3), 3.27 (t, JH-H = 12.0 Hz, 2H, CH2), 3.60 (t, JH-H = 12.0
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Hz, 2H, CH2), 4.50 – 4.58 (m, 2H, 2 × NH). C{1H} NMR (75 MHz, DMSO-d6): δ 14.2 (2 ×
CH3), 19.9 (2 × CH2), 33.9 (d, 3JC-P = 5.0 Hz, 2 × CH2), 34.7 (CH3), 39.5 (2 × CH2), 52.8 (d, 3JC-
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= 18.1 Hz, CH2), 53.6 (d, JC-P = 5.0 Hz, CH2), 165.0 (d, JC-P = 173.1 Hz, C). P NMR (121
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MHz, DMSO-d6): δ 7.08. HRMS (ESI) for C12H28N4OP ([M+H]+): calcd 275.1995, found
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(1-Methyl-4,5-dihydro-1H-imidazol-2-yl)dimorpholinophosphine oxide (3j). The general
procedure A was followed. Purification by column chromatography afforded product as colorless
oil (200 mg, 47%), Rf = 0.18 (CHCl3 : MeOH, 20:1). 1H NMR (600 MHz, DMSO-d6): δ 3.01 (s,
3H, CH3), 3.01 – 3.06 (m, 8H, 4 × CH2), 3.23 (t, JH-H = 10.0 Hz, 2H, CH2), 3.51 – 3.57 (m, 8H, 4
× CH2), 3.68 (t, JH-H = 10.0 Hz, 2H, CH2). 13C{1H} NMR (150 MHz, DMSO-d6): δ 34.7 (CH3),
44.2 (4 × CH2), 52.7 (d, 3JC-P = 4.2 Hz, CH2), 54.5 (d, 3JC-P = 20.0 Hz, CH2), 66.8 (d, 2JC-P = 5.2
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Hz, 4 × CH2), 161.9 (d, JC-P = 184.1 Hz, C). P NMR (243 MHz, DMSO-d6): δ 12.41. HRMS
(ESI) for C12H24N4O3P ([M+H]+): calcd 303.1581, found 303.1579.
Di(phenylamino)(1,4,5,6-tetrahydropyrimidin-2-yl)phosphine oxide (4a). The general procedure
A was followed. Purification by column chromatography afforded product as pale yellow solid
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(366 mg, 83%), m.p. 193 – 195 C, Rf = 0.30 (CHCl3 : MeOH, 10:1). H NMR (300 MHz,
DMSO-d6): δ 1.60 – 1.67 (m, 2H, CH2), 3.25 (t, JH-H = 8.0 Hz, 4H, 2 × CH2), 6.88 (t, JH-H = 8.0
Hz, 2H, 2 × CH), 7.12 – 7.20 (m, 8H, 8 × CH), 8.20 (br. s, 2H, 2 × NH), signal of NH group was
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not observed. C{1H} NMR (75 MHz, DMSO-d6): δ 19.3 (CH2), 40.8 (d, JC-P = 11.1 Hz, 2 ×
CH2), 118.7 (d, 3JC-P = 7.0 Hz, 4 × CH), 121.6 (2 × CH), 129.4 (4 × CH), 141.0 (2 × C), 156.0 (d,
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1JC-P = 185.1 Hz, C). P NMR (121 MHz, DMSO-d6): δ -2.45. HRMS (ESI) for C16H20N4OP
([M+H]+): calcd 315.1369, found 315.1374. IR (KBr): 3252, 3052, 2957, 2875, 1639, 1600,
1499, 1413, 1319, 1284, 1227, 1081, 1031, 938, 750, 691, 563, 486 cm-1.
Di(n-butylamino)(1,4,5,6-tetrahydropyrimidin-2-yl)phosphine oxide (4b). The general procedure
A was followed. Purification by column chromatography afforded product as pale yellow solid
(169 mg, 44%), m.p. 86 - 87 oC, Rf = 0.12 (CHCl3 : MeOH, 10:1). 1H NMR (300 MHz, DMSO-
d6): δ 0.84 (t, JH-H = 8.0 Hz, 6H, 2 × CH3), 1.22 – 1.29 (m, 4H, 2 × CH2), 1.33 – 1.40 (m, 4H, 2 ×
CH2), 1.60 – 1.67 (m, 2H, CH2), 2.68 – 2.76 (m, 4H, 2 × CH2), 3.20 (t, JH-H = 8.0 Hz, 4H, 2 ×
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CH2), 4.42 – 4.50 (m, 2H, 2 × NH), signal of NH group was not observed. C{1H} NMR (75
2
MHz, DMSO-d6): δ 14.2 (2 × CH3), 20.0 (2 × CH2), 20.2 (CH2), 34.1 (d, JC-P = 5.0 Hz, 2 ×
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CH2), 39.6 (2 × CH2), 41.1 (d, JC-P = 11.1 Hz, 2 × CH2), 157.0 (d, JC-P = 183.1 Hz, C). P
NMR (121 MHz, DMSO-d6): δ 10.51. HRMS (ESI) for C12H28N4OP ([M+H]+): calcd 275.1995,
found 275.1992. IR (KBr): 3298, 3228, 2958, 2932, 2872, 1637, 1602, 1506, 1465, 1443, 1362,
1316, 1206, 1162, 1098, 1038, 971, 858, 599, 518 cm-1.
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Di(tert-butylamino)(1,4,5,6-tetrahydropyrimidin-2-yl)phosphine oxide (4c). The general
procedure B was followed. Purification by column chromatography afforded product as pale
yellow solid (300 mg, 78%), m.p. 183 – 186 oC, Rf = 0.10 (CHCl3 : MeOH, 5:1). 1H NMR (300
MHz, DMSO-d6): δ 1.21 (s, 18H, 6 × CH3), 1.55 – 1.62 (m, 2H, CH2), 3.21 (t, JH-H = 6.0 Hz, 4H,
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2 × CH2), 3.95 (br. s, 2H, 2 × NH), signal of NH group was not observed. C{1H} NMR (75
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MHz, DMSO-d6): δ 20.3 (CH2), 31.9 (d, JC-P = 4.0 Hz, 6 × CH3), 41.4 (d, JC-P = 11.1 Hz, 2 ×
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CH2), 50.9 (2 × C), 158.9 (d, JC-P = 191.1 Hz, C). P NMR (121 MHz, DMSO-d6): δ 4.78.
HRMS (ESI) for C12H28N4OP ([M+H]+): calcd 275.1995, found 275.2007. IR (KBr): 3423,
3229, 2969, 2931, 2870, 1603, 1440, 1389, 1364, 1314, 1251, 1229, 1191, 1024, 868 cm-1.
Dimorpholino(1,4,5,6-tetrahydropyrimidin-2-yl)phosphine oxide (4d). The general procedure A
was followed. Purification by column chromatography afforded product as pale yellow solid
o
1
(288 mg, 68%), m.p. 143 – 144 C, Rf = 0.25 (CHCl3 : MeOH, 5:1). H NMR (300 MHz,
DMSO-d6): δ 1.58 – 1.64 (m, 2H, CH2), 2.96 – 3.04 (m, 8H, 4 × CH2), 3.23 (t, JH-H = 8.0 Hz, 4H,
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2 × CH2), 3.47 – 3.55 (m, 8H, 4 × CH2), signal of NH group was not observed. C{1H} NMR
(75 MHz, DMSO-d6): δ 20.2 (CH2), 41.4 (2 × CH2), 44.0 (4 × CH2), 66.4 (d, 2JC-P = 5.0 Hz, 4 ×
CH2), 152.4 (d, 1JC-P = 202.2 Hz, C). 31P NMR (121 MHz, DMSO-d6): δ 15.35. HRMS (ESI) for
C12H24N4O3P ([M+H]+): calcd 303.1581, found 303.1572. IR (KBr): 3301, 2952, 2922, 2854,
2361, 2342, 1608, 1499, 1356, 1319, 1299, 1259, 1176, 1112, 1089, 962, 915, 846, 740, 700,
611, 554, 502 cm-1.
Di(diethylamino)(1,4,5,6-tetrahydropyrimidin-2-yl)phosphine oxide (4e). The general procedure
B was followed. Purification by column chromatography afforded product as colorless oil (246
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mg, 65%), Rf = 0.31 (CHCl3 : MeOH, 10:1). H NMR (300 MHz, DMSO-d6): δ 1.03 (t, JH-H
=
=
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7.0 Hz, 12H, 4 × CH3), 1.63 – 1.70 (m, 2H, CH2), 2.96 – 3.05 (m, 8H, 4 × CH2), 3.26 (t, JH-H
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6.5 Hz, 4H, 2 × CH2), signal of NH group was not observed. C{1H} NMR (75 MHz, DMSO-
d6): δ 14.0 (4 × CH3), 19.6 (CH2), 38.2 (d, 2JC-P = 4.0 Hz, 4 × CH2), 41.2 (d, 3JC-P = 9.1 Hz, 2 ×
CH2), 156.0 (d, 1JC-P = 185.1 Hz, C). 31P NMR (121 MHz, DMSO-d6): δ 16.99. HRMS (ESI) for
C12H28N4OP ([M+H]+): calcd 275.1995, found 275.2006.
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(Methylphenylamino)(azepano)(1,4,5,6-tetrahydropyrimidin-2-yl)phosphi-ne oxide (4f). The
general procedure B was followed. Purification by column chromatography afforded product as
pale yellow oil (318 mg, 68%), Rf = 0.31 (CH2Cl2 : MeOH, 5:1). 1H NMR (300 MHz, CDCl3): δ
1.63 – 1.25 (m, 8H, 4 × CH2), 1.98 – 1.81 (m, 2H, CH2), 3.29 – 3.04 (m, 7H, 2 × CH2 + CH3),
3.50 (t, JH-P = 5.5 Hz, 4H, 2 × CH2), 7.18 (t, JH-H = 7.6 Hz, 1H, CH), 7.30 (t, JH-H = 7.6 Hz, 2H, 2
× CH), 7.58 (d, JH-P = 7.6 Hz, 2H, 2 × CH), signal of NH group was not observed. C{1H}
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NMR (75 MHz, CDCl3): δ 17.7 (CH2), 26.4 (2 × CH2), 29.4 (d, 3JC-P = 3.2 Hz, 2 × CH2), 38.1 (d,
2JC-P = 5.8 Hz, 2 × CH2), 39.5 (d, 3JC-P = 5.3 Hz, 2 × CH2), 47.4 (d, 2JC-P = 3.3 Hz, CH3), 127.5 –
126.5 (m, 4 × CH), 129.4 (CH), 142.4 (d, 2JC-P = 3.7 Hz, C), 158.3 (d, 1JC-P = 159.8 Hz, C). 31P
NMR (121 MHz, CDCl3): δ 10.53. HRMS (ESI) for C17H28N4OP ([M+H]+): calcd 335.1995,
found 335.1986.
(5,5-Dimethyl-1,4,5,6-tetrahydropyrimidin-2-yl)dimorpholinopho-sphine oxide (4g). The general
procedure A was followed. Purification by column chromatography afforded product as pale
yellow solid (263 mg, 57%), m.p. 124 – 125 oC, Rf = 0.15 (CHCl3 : MeOH, 10:1). 1H NMR (300
MHz, DMSO-d6): δ 0.86 (s, 6H, 2 × CH3), 2.89 (s, 4H, 2 × CH2), 3.00 – 3.05 (m, 8H, 4 × CH2),
3.49 – 3.53 (m, 8H, 4 × CH2), signal of NH group was not observed. C{1H} NMR (75 MHz,
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DMSO-d6): δ 25.3 (2 × CH3), 25.9 (C), 44.4 (4 × CH2), 53.7 (2× CH2), 66.8 (d, 2JC-P = 5.0 Hz, 4
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× CH2), 151.7 (d, JC-P = 201.2 Hz, C). P NMR (121 MHz, DMSO-d6): δ 14.41. HRMS (ESI)
for C14H28N4O3P ([M+H]+): calcd 331.1894, found 331.1887. IR (KBr): 3274, 2964, 2906, 2854,
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1607, 1492, 1466, 1387, 1356, 1283, 1239, 1208, 1198, 1181, 1113, 1091, 967, 916, 844, 737,
308, 617, 507, 477, 453 cm-1.
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1-(Dimorpholinophosphoryl)-N-(2-((5-nitropyridin-2-yl)amino)ethyl)methanethioamide (5a). A
mixture of N1-(5-nitropyridin-2-yl)ethane-1,2-diamine (0.17 g, 0.94 mmol, 1.5 equiv) and
elemental sulfur (0.10 g, 3.13 mmol, 5 equiv) in DMF (2.0 mL) was stirred for 30 min at r.t.
After triethylamine (0.40 mL, 2.88 mmol, 4.6 equiv) and 4,4'-chloromethylphosphonoyl-bis-
morpholine (0.17 g, 0.63 mmol, 1 equiv) were added and resulting mixture was stirred for 5 h at
45 oC in an oil bath. Resulting mixture was concentrated under reduced pressure and residue was
extracted with CHCl3 (3 × 30 mL). Combined organic fraction was concentrated under reduced
pressure and product was isolated by column chromatography (eluent CHCl3 → CHCl3:MeOH,
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60:1) to get product as yellow solid (42 mg, 15%) with m.p. 180 – 181 C, Rf = 0.60 (CHCl3 :
MeOH, 10:1). 1H NMR (300 MHz, DMSO-d6): δ 2.92 – 3.08 (m, 8H, 4 × CH2), 3.44 – 3.55 (m,
8H, 4 × CH2), 3.68 – 3.78 (m, 2H, CH2), 3.82 – 3.89 (m, 2H, CH2), 6.56 (d, JH-H = 8.0 Hz, 1H,
CH), 8.12 (d, JH-H = 8.0 Hz, 1H, CH), 8.22 (br. s, 1H, NH), 8.92 (s, 1H, CH), 10.71 (br. s, 1H,
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NH). C{1H} NMR (75 MHz, DMSO-d6): δ 39.0 (CH2), 44.8 (4 × CH2), 45.5 (CH2), 66.5 (d,
2JC-P = 5.0 Hz, 4 × CH2), 109.2 (CH), 132.3 (CH), 135.0 (C), 147.2 (CH), 161.1 (C), 196.5 (d,
1JC-P = 140.9 Hz, C). 31P NMR (121 MHz, DMSO-d6): δ 12.96. HRMS (ESI) for C16H26N6O5PS
([M+H]+): calcd 445.1418, found 445.1418. IR (KBr): 3295, 3244, 3187, 3116, 3083, 2962,
2914, 2849, 1612, 1585, 1545, 1500, 1478, 1332, 1293, 1255, 1186, 1113, 1090, 1006, 970, 911,
851, 733, 711, 660, 595, 514 cm-1.
N-(4-Aminobutyl)-1-(dimorpholinophosphoryl)methane-thioamide (5b). The general procedure
A was followed. Purification by column chromatography afforded product as viscous yellow oil
(331 mg, 68%), Rf = 0.12 (CHCl3 : MeOH, 10:1). 1H NMR (300 MHz, DMSO-d6): δ 1.30 – 1.37
(m, 2H, CH2), 1.57 – 1.63 (m, 2H, CH2), 2.53 (t, JH-H = 8.0 Hz, 2H, CH2), 2.98 – 3.12 (m, 8H, 4
× CH2), 3.49 – 3.55 (m, 8H, 4 × CH2), 3.61 (t, JH-H = 8.0 Hz, 2H, CH2), signals of NH and NH2
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groups were not observed. C{1H} NMR (75 MHz, DMSO-d6): δ 24.8 (CH2), 30.5 (CH2), 41.3
(CH2), 44.9 (4 × CH2), 45.0 (d, 3JC-P = 7.0 Hz, CH2), 66.7 (d, 2JC-P = 7.0 Hz, 4 × CH2), 195.5 (d,
1JC-P = 143.9 Hz, C). 31P NMR (121 MHz, DMSO-d6): δ 13.15. HRMS (ESI) for C13H28N4O3PS
([M+H]+): calcd 351.1614, found 351.1606.
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N-(5-Aminopentyl)-1-(dimorpholinophosphoryl)methane-thioamide (5c). The general procedure
A was followed. Purification by column chromatography afforded product as viscous yellow oil
(250 mg, 49%), Rf = 0.14 (CHCl3 : MeOH, 10:1). 1H NMR (600 MHz, DMSO-d6): δ 1.20 – 1.29
(m, 2H, CH2), 1.30 – 1.37 (m, 2H, CH2), 1.55 – 1.62 (m, 2H, CH2), 2.52 (t, JH-H = 8.0 Hz, 2H,
CH2), 2.98 – 3.07 (m, 4H, 2 × CH2), 3.07 – 3.12 (m, 4H, 2 × CH2), 3.50 – 3.57 (m, 8H, 4 × CH2),
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3.62 (t, JH-H = 8.0 Hz, 2H, CH2), signals of NH and NH2 groups were not observed. C{1H}
NMR (150 MHz, DMSO-d6): δ 24.3 (CH2), 27.0 (CH2), 33.0 (CH2), 39.7 (CH2), 44.4 (4 × CH2),
44.5 (d, 3JC-P = 15.0 Hz, CH2), 66.7 (d, 2JC-P = 5.0 Hz, 4 × CH2), 196.8 (d, 1JC-P = 135.0 Hz, C).
31P NMR (243 MHz, DMSO-d6): δ 13.01. HRMS (ESI) for C14H30N4O3PS ([M+H]+): calcd
365.1771, found 365.1769.
N-(6-Aminohexyl)-1-(dimorpholinophosphoryl)me-thanethioamide (5d). The general procedure
A was followed. Purification by column chromatography afforded product as viscous yellow oil
(359 mg, 68%), Rf = 0.19 (CHCl3 : MeOH, 10:1). 1H NMR (300 MHz, DMSO-d6): δ 1.20 – 1.28
(m, 4H, 2 × CH2), 1.28 – 1.37 (m, 2H, CH2), 1.56 – 1.61 (m, 2H, CH2), 2.52 (t, JH-H = 8.0 Hz,
2H, CH2), 2.98 – 3.12 (m, 8H, 4 × CH2), 3.49 – 3.58 (m, 8H, 4 × CH2), 3.61 (t, JH-H = 8.0 Hz,
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2H, CH2), signals of NH and NH2 groups were not observed. C{1H} NMR (75 MHz, DMSO-
d6): δ 26.5 (CH2), 26.8 (CH2), 27.2 (CH2), 33.1 (CH2), 41.7 (CH2), 44.3 (CH2), 44.4 (4 × CH2),
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66.7 (d, JC-P = 4.0 Hz, 4 × CH2), 195.8 (d, JC-P = 195.2 Hz, C). P NMR (121 MHz, DMSO-
d6): δ 13.08. HRMS (ESI) for C15H32N4O3PS ([M+H]+): calcd 379.1927, found 379.1922.
General method for synthesis of compounds 6. Diamine 2 (0.43 mmol, 1.0 equiv) was added
to the suspension of сhloromethylphosphonic acid bisdiethyl amide 1 (100 mg, 0.43 mmol, 1.0
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equiv), elemental sulfur (41 mg, 1.29 mmol, 3.0 equiv), and DIPEA (224 µL, 1.29 mmol, 3.0
equiv) in water (1 mL). The mixture was refluxed for 5 h in an oil bath until the complete
conversion of phosphinic chloride (TLC monitoring). The resulted mixture was cooled to r.t.,
diluted with water (20 mL), carefully acidified with 2% HCl until pH 7 and extracted with
CH2Cl2 (3 x 7 mL). Combined organic layers dried over Na2SO4, solvent was removed under
reduced pressure and product was isolated by column chromatography.
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N,N'-(Propane-1,3-diyl)bis(1-(bis(diethylamino)phos-phoryl)methanethioamide)
(6a).
The
general procedure was followed using 31 mg (35 μL) of propane-1,3-diamine. Purification by
column chromatography (eluent CH2Cl2 – MeOH, 1:0 → 50:1) afforded product as a yellow
solid (65 mg, 58%), m.p. 151 – 153 оС, Rf = 0.19 (CH2Cl2 : MeOH, 25:1). 1H NMR (300 MHz,
CDCl3): δ 9.71 (br. s, 2H, 2 × NH), 3.84 – 3.70 (m, 4H, 2 × CH2), 3.14 (dq, JH-P = 10.7 Hz, JH-H
= 7.1 Hz, 16H, 8 × CH2), 2.16 – 1.99 (m, 2H, CH2), 1.10 (t, JH-H = 7.1 Hz, 24H, 8 × CH3).
13C{1H} NMR (75 МHz, CDCl3): δ 199.7 (d, 1JC-P = 142.2 Hz, 2 × C), 42.2 (d, 3JC-P = 7.1 Hz, 2
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× CH2), 38.6 (d, JC-P = 3.9 Hz, 8 × CH2), 26.2 (CH2), 13.5 (d, JC-P = 2.9 Hz, 8 × CH3). P
NMR (121 МHz, CDCl3): δ 18.03. HRMS (ESI) for C21H49N6O2P2S2 ([M+H]+): calcd 543.2824,
found 543.2828.
N,N'-(2,2-Dimethylpropane-1,3-diyl)bis(1-(bis(diethylamino)phosphoryl)methanethio-amide)
(6b). The general procedure was followed using 42 mg (50 μL) of 2,2-dimethylpropane-1,3-
diamine. Purification by column chromatography (eluent CH2Cl2 : MeOH, 1:0 → 75:1) afforded
о
product as a yellow solid (23 mg, 19%), m.p. 158 – 160 С, Rf = 0.31 (CH2Cl2 : MeOH, 25:1).
1H NMR (300 МHz, CDCl3): δ 9.86 (br. s, 2H, 2 × NH), 3.69 (d, JH-P = 6.0 Hz, 2H, 2 × CH2),
3.16 (dq, JH-P = 17.2 Hz, JH-H = 7.6 Hz, 16H, 8 × CH2), 1.11 (t, JH-H = 7.1 Hz, 24H, 8 × CH3),
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1.09 (s, 6H, 2 × CH3). C{1H} NMR (75 МHz, CDCl3): δ 200.5 (d, JC-P = 142.5 Hz, 2 × C),
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51.4 (d, JC-P = 7.1 Hz, 2 × CH2), 38.7 (d, JC-P = 4.1 Hz, 8 × CH2), 38.2 (C), 23.8 (2 × CH3),
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13.5 (d, JC-P = 3.0 Hz, 8 × CH3). 31P NMR (121 МHz, CDCl3): δ 18.37. HRMS (ESI) for
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C23H53N6O2P2S2 ([M+H]+): calcd 571.3141, found 571.3141.
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N,N'-(Butane-1,4-diyl)bis(1-(bis(diethylamino)-phosphoryl)methanethioamide) (6c). The general
procedure was followed using 37 mg (42 μL) of bytane-1,4-diamine. Purification by column
chromatography (eluent CH2Cl2 : MeOH, 1:0 → 75:1) afforded product as a yellow solid (46
mg, 40%), m.p. 168 – 170 оС, Rf = 0.30 (CH2Cl2 : MeOH, 25:1). 1H NMR (300 МHz, CDCl3): δ
9.59 (br. s, 2H, 2 × NH), 3.77 – 3.64 (m, 4H, 2 × CH2), 3.12 (dq, JH-P = 10.7 Hz, JH-H = 7.1 Hz,
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16H, 8 × CH2), 1.81 – 1.69 (m, 4H, 2 × CH2), 1.09 (t, JH-H = 7.1 Hz, 24H, 8 × CH3). C{1H}
NMR (75 МHz, CDCl3): δ 199.2 (d, 1JC-P = 141.9 Hz, 2 × C), 44.4 (d, 3JC-P = 7.1 Hz, 2 × CH2),
38.6 (d, 2JC-P = 4.1 Hz, 8 × CH2), 29.7 (CH2), 25.1 (CH2), 13.4 (d, 3JC-P = 3.0 Hz, 8 × CH3). 31P
NMR (121 МHz, CDCl3): δ 18.92. HRMS (ESI) for C22H51N6O2P2S2 ([M+H]+): calcd 557.2982,
found 557.2985.
N,N'-(Pentane-1,5-diyl)bis(1-(bis(diethylamino)-phosphoryl)methanethioamide)
(6d).
The
general procedure was followed using 42 mg (49 μL) of pentane-1,5-diamine. Purification by
column chromatography (eluent CH2Cl2 : MeOH, 1:0 → 75:1) afforded product as a yellow solid
(74 mg, 62%), m.p. 96 – 98 оС, Rf = 0.23 (CH2Cl2 : MeOH, 25:1). 1H NMR (300 МHz, CDCl3):
δ 9.53 (br. s, 2H, 2 × NH), 3.74 – 3.60 (m, 4H, 2 × CH2), 3.13 (dq, JH-P = 10.7 Hz, JH-H = 7.1 Hz,
16H, 8 × CH2), 1.82 – 1.64 (m, 4H, 2 × CH2), 1.54 – 1.36 (m, 2H, CH2), 1.10 (t, JH-H = 7.1 Hz,
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24H, 8 × CH3). C{1H} NMR (75 МHz, CDCl3): δ 199.0 (d, JC-P = 141.7 Hz, 2 × C), 44.7 (d,
3JC-P = 6.9 Hz, 2 × CH2), 38.6 (d, 2JC-P = 4.0 Hz, 8 × CH2), 27.2 (2 × CH2), 24.4 (CH2), 13.4 (d,
3JC-P = 2.9 Hz, 8 × CH3). 31P NMR (121 МHz, CDCl3): δ 18.07. HRMS (ESI) for
C23H53N6O2P2S2 ([M+H]+): calcd 571.3156, found 571.3141.
N,N'-(Hexane-1,6-diyl)bis(1-(bis(diethylamino)-phosphoryl)methanethioamide)
(6e).
The
general procedure was followed using 48 mg of hexane-1,6-diamine. Purification by column
chromatography (eluent CH2Cl2 : MeOH, 1:0 → 75:1) afforded product as a yellow solid (96
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mg, 79%), m.p. 110 – 112 оС, Rf = 0.31 (CH2Cl2 : MeOH, 25:1). 1H NMR (300 МHz, CDCl3): δ
9.53 (br. s, 2H, 2 × NH), 3.70 – 3.55 (m, 4H, 2 × CH2), 3.10 (dq, JH-P = 10.8 Hz, JH-H = 7.1 Hz,
16H, 8 × CH2), 1.73 – 1.56 (m, 4H, 2 × CH2), 1.45 – 1.31 (m, 4H, 2 × CH2), 1.07 (t, JH-H = 7.1
Hz, 24H, 8 × CH3). 13C{1H} NMR (75 МHz, CDCl3): δ 198.8 (d, 1JC-P = 141.8 Hz, 2 × C), 44.8
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(d, JC-P = 6.9 Hz, 2 × CH2), 38.6 (d, JC-P = 4.0 Hz, 8 × CH2), 27.4 (2 × CH2), 26.6 (2 × CH2),
13.4 (d, JC-P = 2.9 Hz, 8 × CH3). 31P NMR (121 МHz, CDCl3): δ 18.04. HRMS (ESI) for
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C24H55N6O2P2S2 ([M+H]+): calcd 585.3309, found 585.3298.
N,N'-(Heptane-1,7-diyl)bis(1-(bis(diethylamino)-phosphoryl)methanethioamide)
(6f).
The
general procedure was followed using 56 mg of heptane-1,7-diamine. Purification by column
chromatography (eluent CH2Cl2 : MeOH, 1:0 → 75:1) afforded product as a yellow solid (91
mg, 71%), m.p. 108 – 110 оС, Rf = 0.21 (CH2Cl2 : MeOH, 25:1). 1H NMR (300 МHz, CDCl3): δ
9.48 (br. s, 2H, 2 × NH), 3.77 – 3.60 (m, 4H, 2 × CH2), 3.16 (dq, JH-P = 10.7 Hz, JH-H = 7.1 Hz,
16H, 8 × CH2), 1.75 – 1.64 (m, 4H, 2 × CH2), 1.45 – 1.34 (m, 2H, CH2), 1.42 – 1.35 (m, 4H, 2 ×
CH2), 1.12 (t, JH-H = 7.1 Hz, 24H, 8 × CH3). 13C{1H} NMR (75 МHz, CDCl3): δ 198.8 (d, 1JC-P
=
141.7 Hz, 2 × C), 45.0 (d, 3JC-P = 6.9 Hz, 2 × CH2), 38.6 (d, 2JC-P = 4.0 Hz, 8 × CH2), 28.8 (CH2),
27.5 (2 × CH2), 26.9 (2 × CH2), 13.4 (d, 3JC-P = 2.9 Hz, 8 × CH3). 31P NMR (121 МHz, CDCl3):
δ 18.13. HRMS (ESI) for C25H57N6O2P2S2 ([M+H]+): calcd 599.3460, found 599.3454.
N,N'-(Octane-1,8-diyl)bis(1-(bis(diethyl-amino)phosphoryl)methanethioamide) (6g). The general
procedure was followed using 56 mg of octane-1,8-diamine. Purification by column
chromatography (eluent CH2Cl2 : MeOH, 1:0 → 75:1) afforded product as a yellow solid (111
mg, 87%), m.p. 115 – 117 оС, Rf = 0.31 (CH2Cl2 : MeOH, 25:1). 1H NMR (300 МHz, CDCl3): δ
9.54 (br. s, 2H, 2 × NH), 3.67 – 3.52 (m, 4H, 2 × CH2), 3.07 (dq, JH-P = 10.8 Hz, JH-H = 7.1 Hz,
16H, 8 × CH2), 1.69 – 1.53 (m, 4H, 2 × CH2), 1.35 – 1.22 (m, 8H, 2 × CH2 + 2 × CH2), 1.04 (t,
JH-H = 7.1 Hz, 24H, 8 × CH3). 13C{1H} NMR (75 МHz, CDCl3): δ 198.6 (d, 1JC-P = 141.8 Hz, 2 ×
C), 44.9 (d, 3JC-P = 6.9 Hz, 2 × CH2), 38.6 (d, 2JC-P = 3.9 Hz, 8 × CH2), 29.0 (2 × CH2), 27.5 (2 ×
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CH2), 26.9 (2 × CH2), 13.4 (d, JC-P = 2.9 Hz, 8 × CH3). P NMR (121 МHz, CDCl3): δ 18.02.
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HRMS (ESI) for C26H59N6O2P2S2 ([M+H]+): calcd 613.3607, found 613.3611.
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Scaled-up synthesis of (4,5-dihydro-1H-imidazol-2-yl)dimorpholinophosphine oxide (3d).
A mixture of 1,2-ethylenediamine 2a (6.5 mL, 98 mmol, 14 equiv) and elemental sulfur (1.1 g,
35.0 mmol, 5 equiv) was stirred for 30 min at r.t. Phosphinic chloride 1d (2.0 g, 7.0 mmol, 1
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o
equv) was added and resulting mixture was additionally stirred for 7 h at 40 C in an oil bath
until the complete conversion of phosphinic chloride (TLC monitoring). The resulted mixture
was cooled to r.t. and viscous oil was extracted with MeOH (3 × 20 mL). Combined organic
fraction was concentrated under reduced pressure and product was isolated by column
chromatography (eluent CHCl3 : MeOH, 2:1) to get pale yellow solid (1.6 g, 79%).
■ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Сopies of 1H,13C, and 31P NMR spectra for compounds 1,3-6 (PDF).
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: yavolkova@gmail.com
ORCID
Igor V. Zavarzin 0000-0002-8194-5756
Yulia A. Volkova 0000-0001-8554-838X
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
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■ ACKNOWLEDGMENT
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The research is supported by the Russian Science Foundation (grant No. 18-73-00321).
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