Synthesis of 4,5-dihydroimidazo[5,1-c][1,4,2]benzodiazaphosphinines

Article abstract of DOI:10.1002/hc.20658

Derivatives of a novel phosphoruscontaining heterocyclic system, 4,5-dihydroimidazo [5,1-c][1,4,2]benzodiazaphosphinine, have been prepared by the direct phosphorylation of 1-(2-(aroyl/alkyl)aminophenyl)-2- methylthioimidazole with dibromophenylphosphine

Full text of DOI:10.1002/hc.20658

Heteroatom Chemistry
Volume 22, Number 1, 2011
Synthesis of 4,5-Dihydroimidazo[5,1-
c][1,4,2]benzodiazaphosphinines
Evgeniy V. Zarudnitskii, Andrey A. Kyrylchuk, Anastasiia N.
Huryeva, Aleksandr N. Kostyuk, and Aleksandr A. Yurchenko
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kyiv-94, 02094, Ukraine
Received 28 July 2010; revised 13 October 2010
on imidazole, pyrazole, thiophene, and furan were
ABSTRACT: Derivatives of a novel phosphorus-
synthesized [4,5,6].
containing heterocyclic system, 4,5-dihydroimidazo
We have shown that phosphorylation of
[5,1-c][1,4,2]benzodiazaphosphinine, have been pre-
N-alkyl (aryl) substituted imidazoles proceeds at the
pared by the direct phosphorylation of 1-(2-(aroyl/
2-position. If the second position of the imidazoles
alkyl)aminophenyl)-2-methylthioimidazole with di-
is occupied, the phosphorylation is directed at the
ꢀ
C
bromophenylphosphine in a basic medium.
2010
fifth position [3]. Thus, a series of 5-phosphorylated
imidazoles with a trivalent and pentavalent phos-
phorus atom was synthesized, among which the
5-dichlorophosphino-derivatives of 1,2-disubstitued
imidazoles are the most considerable as the first rep-
resentative of dihalophosphines in the series of imi-
dazoles.
Wiley Periodicals, Inc. Heteroatom Chem 22:91–95, 2011;
View this article online at wileyonlinelibrary.com. DOI
10.1002/hc.20658
INTRODUCTION
In this paper, we explore a possibility of
applying the same strategy for the synthesis
C-Phosphorylated imidazoles attract a great deal of
attention due to their diverse biological activity. In
addition, their P(III) derivatives can be prospective
ligands for metal complex catalysis [1,2].
of
a novel phosphorus-containing heterocyclic
system—that is, 4,5-dihydrobenzo[e]imidazo[5,1-
c][1,4,2]diazaphosphinine. As a substrate, we use the
imidazole in which the second position is blocked by
a methylthio group and the second N-nucleophilic
center is places on the phenyl ring, thus allowing
formation of cyclic products with biselectrophiles.
Earlier we found a convenient method for the
preparation of phosphorylated imidazoles using
phosphorus(III) halides in a basic medium [3]. This
approach is widely used in a synthetic strategy,
allowing synthesis of phosphorus-containing fused
heterocyclic systems that are not very accessible
by other routes. The approach is based on direct
phosphorylation of a substrate containing two nu-
cleophilic centers: electron-rich aryl or heteroaryl
C-nucleophilic center and other nucleophilic het-
eroatom (N, O). Various polycyclic systems based
RESULTS AND DISCUSSION
The
suitable
starting
compounds—
(Scheme 1) and
(Scheme 2)—are
acylaminophenylimidazole
alkylaminophenylimidazole
5
7
not described in the literature, so we have syn-
thesized them starting from o-nitroaniline.
A
one-pot two-step treatment of o-nitroaniline 1
with thiophosgene in the presence of HCl and
2-aminoacetaldehyde diethylacetal gave imidazole
Correspondence to: Aleksandr N. Kostyuk; e-mail: a.kostyuk@
enamine.net.
2010 Wiley Periodicals, Inc.
c
ꢀ
91

92 Zarudnitskii et al.
H
N
N
1) CSCl2, HCl
NH2
S
MeI
S
FeSO4, NH3 (aq.)
N
2) (EtO)2CHCH2NH
NO2
N
2 O2N
O2N
1
2
3
Cl
O
N
N
Cl
Cl
S
N
H
S
N
N
H2N
C5H5N
O
5
4
SCHEME 1
N
N
N
S
S
LiAlH4
THF
S
N
HCOOH
N
N
H
N
N
H2N
O
H
4
7
6
SCHEME 2
1
2. Methylation of the SH-group with methyl iodide
afforded 2-methylthioimidazole 3, and its reduction
with FeSO4/ammonium hydroxide gave rise to
aminophenyl-methylthioimidazole 4. Acylation
of the latter with 4-chlorophenylcarboxylic acid
chloride in pyridine afforded derivative 5.
1-(2-Methylaminophenyl)-2-methylthioimida-
zole 7 was obtained from imidazole 4 by formy-
lation with 85% aqueous formic acid and subse-
quent reduction with lithium aluminum hydride in
THF.
C(5)-H and NH-protons of the imidazoles in the H
NMR spectra.
N
N
Cl
S
P
N
N
S
N
PhPBr2, Et3N
Py
H
N
O
O
We have found that imidazole derivative 5 reacts
with dibromophenylphosphine in pyridine medium
in the presence of two equivalents of triethylamine
giving rise to diazaphosphinine 8 in high yield (see
Scheme 3).
5
Cl
8
Diazaphosphinine 8 was isolated as white crys-
tals, which are poorly soluble in benzene and diethyl
ether.
SCHEME 3
Synthesis of compound 9 was carried out anal-
ogously. As it was impossible to purify the target
compound 9 to an analytically pure sample, it was
oxidized with hydrogen peroxide to its oxide 10. Ex-
traction and recrystallization gave product 10 in 33%
yield as yellowish air-stable crystals (see Scheme 4).
The cyclization of the starting aminoimida-
zoles was confirmed by disappearance of signals of
N
N
N
O
P
N
PhPBr2
Py
S
N
S
H2O2
S
N
P
N
N
N
10
7
9
SCHEME 4
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of 4,5-Dihydroimidazo[5,1-c][1,4,2]benzodiazaphosphinines 93
CONCLUSION
7.73 (t, J = 7 Hz, 1H, H-4 Ph), 7.88 (t, J = 9 Hz,
1H, H-5 Ph), 8.16 (d, J = 7.5 Hz, 1H, H-3 Ph),
12.43 (br-s, 1H, SH). 13C NMR (DMSO-d6/TMS): δ
(ppm) 116.24, 116.39, 120.11, 125.75, 130.63, 130.88,
131.44, 135.11, 146.23, 163.15. NMR spectrum is
consistent with the literature data [7].
We have shown that imidazoles 5 and 7 bearing two
nucleophilic centers, imidazole C5 carbon atom and
NH atom at the phenyl ring, are suitable substrates
for phosphorylation with dibromophenylphosphine.
A novel phosphorus-containing heterocyclic system,
4, 5-dihydroimidazo[5, 1- c][1, 4, 2]benzodiazaphos-
phinine, has been prepared.
1-(2-Nitrophenyl)-2-methylthioimidazole (3)
Compound 2 (19.1 g, 87.0 mmol) and NaOH (4.0
g, 0.1 mol) were dissolved in methanol (100 mL).
Methyl iodide (5.4 mL, 87.0 mmol) was added to
the solution. After stirring for 2 h at 20◦C, the reac-
tion mixture was evaporated and the residue was ex-
tracted with hot benzene (100 mL). The precipitated
solid was filtered off; the filtrate was evaporated. The
residue was recrystallized from ethanol. Yield: 18.3 g
(90.1%). 1H NMR (CDCl3/TMS): δ (ppm) 2.57 (s, 3H,
SMe), 7.06 (d, J = 1.2 Hz, 1H, H-5 Im), 7.25 (d, J =
1.5 Hz, 1H, H-4 Im), 7.49 (dd, J = 7.8 Hz, J = 1.5 Hz,
1H, H-6 Ph), 7.68 (td, J = 7.8 Hz, J = 1.5 Hz, 1H,
H-4 Ph), 7.80 (td, J = 6 Hz, J = 1.5 Hz, 1H, H-5 Ph),
8.13 (dd, J = 8 Hz, J = 1.2 Hz, 1H, H-3 Ph). MS
(APCI) m/z(%) = 236 [M].
EXPERIMENTAL
All the manipulations with air-sensitive compounds
were performed under an atmosphere of dry argon
using standard Schlenk techniques. Solvents were
purified by conventional procedures. Melting points
were determined with an electrothermal capillary
melting point apparatus and were not corrected.
The 31P, 1H, and l3C NMR spectra were ob-
tained on a Varian VXR-300 spectrometer (125, 300,
and 75 MHz, respectively, if other is not speci-
fied). Chemical shifts are reported relative to in-
ternal tetramethylsilane (1H, 13C) or external 85%
H3PO4 (31P). Mass-spectra were obtained on a MX-
1321 instrument (EI, 70 eV) by a direct inlet.
LC/MS spectra were recorded using an Agilent 1100
series HPLC equipped with diode-matrix and mass-
selective detector Agilent LC\MSD SL. The param-
eters of chromatography–mass analysis: column,
Zorbax SB-C18, 1.8 mm, 4.6 mm × 15 mm; eluent A:
MeCN-H2O with 0.1% of TFA (95:5); eluent B: H2O
with 0.1% of TFA; flow rate, 3 mL/s; volume of in-
jected sample: 1 mL; UV-detectors at 215, 254, and
265 nm; ionization method: chemical ionization un-
der atmospheric pressure (APCI); ionization mode:
simultaneous scanning of positive and negative ions
in the mass range of 80–1000 m/z.
1-(2-Aminophenyl)-2-methylthioimidazole (4)
Aqueous NH3 (20%, 450 mL) was added to methylth-
ioimidazole 3 (9.0 g, 0.04 mol). A solution of
FeSO4·7H2O (65.0 g) in water (80 mL) was added to
the mixture with stirring at 50◦C. The reaction mix-
ture was refluxed for 2 h. Then, water was evaporated
and the residue was extracted with dichloromethane.
Combined extracts were washed with water; the or-
ganic layer was separated, dried, and evaporated.
Yield: 6.0 g (77%). 1H NMR (DMSO-d6/TMS): δ (ppm)
2.46 (s, 3H, SMe), 4.85 (br-s, 2H, NH2), 6.62 (td, J =
7.5, J = 1.4, 1H, H-5 Ph), 6.84 (dd, J = 8.1 Hz, J =
1.2 Hz, 1H, H-3 Ph), 6.97 (dd, J = 6.3 Hz, J = 1.4
Hz, 1H, H-6 Ph), 7.12 (dd, J = 1.2 Hz, 1H, H-5 Im),
7.16 (td, J = 7.2 Hz, J = 1.4 Hz, 1H, H-4 Ph), 7.23
(d, J = 1.4 Hz, 1H, H-4 Im). MS (70 eV) m/z (%): 205
(82.11, M+), 158 (100), 132 (43.25), 131 (45.50), 106
(56.51).
1-(2-Nitrophenyl)-1H-imidazole-2-thiol (2)
o-Nitroaniline 1 (25.0 g, 0.18 mol) was added to hy-
drochloric acid (500 mL, 20%). The resulted mixture
was heated at 50◦C until all o-nitroaniline was dis-
solved. Then, CSCl2 (22.6 g, 0.2 mol) was added and
the reaction mixture was stirred at 20◦C for 4 h. The
precipitate was filtered and added to the solution
of 2-aminoacetaldehyde diethylacetal (24.0 g, 0.18
mol) in ethanol (200 mL). The reaction mixture was
refluxed for 30 min, then ethanol was evaporated.
The residue was refluxed for 1 h with hydrochlo-
ric acid (200 mL, 10%). The precipitated solid was
filtered and crystallized from ethanol. Yield: 41.0
1-(2-(4-Chlorobenzylamino)phenyl)-2-
methylthioimidazole (5)
4-Chlorobenzoylchloride (4.2 g, 0.025 mol) was dis-
solved in dry pyridine (50 mL), and the mixture was
cooled to −10◦C. 5.0 g (25.0 mmol) of compound 4
was added after precipitation of colorless complex.
The reaction mixture was stirred for 4 h at 20◦C.
Then the solution was poured onto ice, the crystals
were filtrated, crystallized from benzene. Yield: 4.3 g
g (28%), mp 202–205◦C. H NMR (DMSO-d6/TMS,
500 MHz): δ (ppm) 7.11 (s, 1H, H-5 Im), 7.31 (s,
1H, H-4 Im), 7.60 (d, J = 8.5 Hz, 1H, H-6 Ph),
1
Heteroatom Chemistry DOI 10.1002/hc

94 Zarudnitskii et al.
1
(51%). H NMR (DMSO-d6/TMS): δ (ppm) 2.43 (s,
5-(4-Chlorobenzoyl)-1-(methylthio)-4-phenyl-4,
5-dihydroimidazo[5,1-c][1,4,2]benzodiazaphos-
phine (8)
3H, SMe), 6.99 (s, 1H, H-5 Im), 7.25 (s, 1H, H-4
Im), 7.41 (d, J = 4 Hz, 2H, H-6, H-3 Ph), 7.53 (m,
3H, H-5 Ph + meta-Cl-C6H4-CO), 7.61 (m, 1H, H-4
Ph), 7.76 (d, J = 8 Hz, 2H, ortho-Cl-C6H4-CO), 9.97
(br-s, 1H, NH). 13C NMR (DMSO-d6/TMS): δ (ppm)
15.64, 122.85, 126.83, 127.84, 127.91, 127.95, 128.40,
128.71, 129.19, 129.42, 129.55, 132.35, 132.40,
132.83, 132.88, 133.39, 133.53, 136.47, 142.53,
164.41, 164.51. MS (70 eV) m/z (%): 343 (16.95, M+),
141 (32.33), 139 (100), 132 (20.23), 111 (40.75).
Dibromophenylphosphine (0.80 g, 3.0 mmol) and
dry triethylamine (0.63 g, 6.2 mmol) were conse-
quently added to a solution of imidazole 5 (1.0 g,
3.0 mmol) in dry pyridine (10 mL) cooled from
◦
−5 to −10◦C. After keeping for 30 h at 2 C, the
pyridine was evaporated in vacuo, the residue was
treated with hot benzene (20 mL), Et3N·HCl pre-
cipitated was filtered under argon, the filtrate was
evaporated, and the residue was extracted with hot
hexane (60 mL). After decantation from the oil, the
extract was evaporated. The residue obtained after
evaporation was treated with ether (30 mL), and
the solid product was collected by filtration. Yield:
1-(2-Formylaminophenyl)-2-methylthioimida-
zole (6)
1
1.2 g (91%), mp 148–149◦C. H NMR (C6D6/TMS):
Imidazole 4 (3.0 g, 14.6 mmol) was added to an
aqueous solution of formic acid (20 mL 85%, 0.44
mol). The reaction mixture was refluxed for 0,5 h.
After cooling to r.t., the solution was evaporated and
the residue was crystallized from MeOH-H2O (1:1).
δ (ppm) 2.50 (s, 1H, SMe), 6.43 (t, J = 6.3 Hz,
1H, H-5 Ph), 6.58 (t, J = 7.8 Hz, 1H, H-4 Ph),
6.75 (m, 6H, P-Ph + H-6 Ph), 7.21 (m, 4H, Cl–
C6H4–CO), 7.52 (s, 1H, H-4 Im), 7.76 (d, J =
8.4 Hz, 1H, H-3 Ph). 13C NMR (CDCl3): δ (ppm)
15.66, 120.75, 125.58, 126.14, 126.81, 126.91, 128.48,
128.61, 129.03, 129.56, 130.97, 131.74, 132.94,
135.73, 137.34, 137.68, 137.98, 146.85, 171.41. 31P
NMR (C6D6): δ (ppm) 5.50. MS (70 eV) m/z (%): 449
(20.17, M+), 325 (37.07), 312 (45,79), 237 (21.33),
139 (100), 111 (48.25).
1
Yield: 2.3 g (68%). H NMR (CDCl3): δ (ppm) 2.52
(s, 3H, SMe), 7.01 (d, 1H, H-4 Im, J = 1,2 Hz),
7.13 (d, 1H, H-5 Im, J = 1,5 Hz), 7.25 (br m, 2H,
H-3,5 Ph), 7.50 (br m, 1H, H-4 Ph), 8.15 (br s, 1H,
NH), 8.46 (d, 1H, H-6 Ph, J = 1,7 Hz), 8.52 (d,
1H, C(O)H, J = 8.4 Hz), 13C NMR (CDCl3): δ (ppm)
15.33, 119.77, 122.00, 122.57, 124.76, 125.94, 128.06,
130.57, 133.90, 145.24, 159.42. MS (70 eV) m/z (%):
233 (100, M+), 186 (78.19), 158 (83.00), 131 (87.02),
106 (86.02). mp 170–175◦C.
1-Ethyl-5-methyl-4-phenyl-4,5-dihydroimidazo
[5,1-c][1,4,2] benzodiazaphosphinine
4-oxide (10)
Compound 7 (0.90 g, 4.0 mmol) was added to a
solution of 1.1 g (4 mmol) of dibromophenylphos-
phine in pyridine (10 mL) to cooled to −30◦C.
The mixture was allowed to warm to r.t. After a
week, the solution was evaporated in vacuum, the
residue was treated with hot benzene, and the pre-
cipitated material was filtrated. The benzene filtrate
was evaporated, and the impurities were extracted
by hot hexane. The residue was dissolved in Et2O
and H2O2 (0.5 mL 35% aq.) was added. The ether
solution was evaporated, and the residue was dis-
solved in dichloromethane and washed with water.
The organic layer was evaporated, and the residue
was extracted with hot benzene, the benzene was
evaporated, and the residue was recrystallized from
ether. Yield: 0.46 g (33%) 1H NMR (CDCl3): δ (ppm)
2.82 (s, 3H, SMe), 3.12 (d, 3H, NMe, J = 8.5 Hz),
7.2 (br m, 2H, H-6 Ph, para-H P-Ph), 7.38 (br t, 1H,
H-5 Ph), 7.45 (br s, 2H, meta-H P-Ph), 7.45 (br m,
2H, H-3,4 Ph), 7.69 (br m, 2H, ortho-H P-Ph), 8.14
(d, 1H, H-4 Im, J = 8 Hz). 13C NMR (CDCl3): δ (ppm)
1 - (2 - Methylaminophenyl) - 2 - methylthioimida-
zole (7)
Lithium aluminum hydride (1.14 g, 0.03 mol) was
added to THF (25 mL), then 2.3 g (9.6 mmol) of
compound 6 was added to the reaction mixture. It
was stirred for 2 h and was quenched with water. The
solution obtained was filtered, the filtrate was evapo-
rated, and the residue was twice recrystallized from
heptane. The product was dried in vacuum. Yield:
1
1.6 g (77%). H NMR (CDCl3, 500 MHz): δ (ppm)
2.59 (s, 3H, SMe), 2.84 (d, 3H, NH-Me, J = 5 Hz),
3,53 (br s, 1H, NH), 6.78 (d, 2H, H-5.6 Ph), 7.02
(d, 1H, H-5 Im, J = 0.5 Hz), 7.10 (d, 1H, H-3 Ph,
J = 7.5 Hz), 7.24 (d, 1H, H-4 Im, J = 1 Hz), 7.38
(t, 1H, H-4 Ph, J = 7.5 Hz). 13C NMR (CDCl3): δ
(ppm) 15.30, 29.99, 111.26, 116.47, 122.07, 122.11,
128.19, 130.03, 130.57, 145.16, 144.96. MS (70 eV)
m/z (%): 219 (23.72, M+), 172 (100.00), 157 (21.81),
145 (23.26), 131 (15.76). mp 137–140◦C.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of 4,5-Dihydroimidazo[5,1-c][1,4,2]benzodiazaphosphinines 95
16.50, 30.41, 30.89, 116.84, 116.80, 120.24, 121.58,
123.03, 124.23, 125.39, 127.77, 128.72, 128.83,
129.95, 131.06, 131.71, 131.80, 132.73, 132.75,
134.27, 135.56, 135.69. 31P NMR (CDCl3): δ (ppm)
9.52. MS (APCI) m/z (%) = 342 [M + 1].
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Heteroatom Chemistry DOI 10.1002/hc