New condensed heterocyclic system with a bridgehead phosphorus atom

Article abstract of DOI:10.1023/A:1015699623518

New condensed heterocyclic system with a bridgehead phosphorus atom has been synthesized by the reaction of imidazolyl anilides of 3,4-dimethoxy- and 3-dimethylaminobenzoic acids with phosphorus(III) halides. The reaction begins with the formation of cyclic halogenophosphonites which are later able to undergo intramolecular heterocyclization to form pentacyclic compounds.

Full text of DOI:10.1023/A:1015699623518

Chemistry of Heterocyclic Compounds, Vol. 38, No. 3, 2002
NEW CONDENSED HETEROCYCLIC
SYSTEM WITH A BRIDGEHEAD
PHOSPHORUS ATOM
V. V. Ivanov, A. A. Yurchenko, A. M. Pinchuk, and A. A. Tolmachev
New condensed heterocyclic system with a bridgehead phosphorus atom has been synthesized by the
reaction of imidazolyl anilides of 3,4-dimethoxy- and 3-dimethylaminobenzoic acids with
phosphorus(III) halides. The reaction begins with the formation of cyclic halogenophosphonites which
are later able to undergo intramolecular heterocyclization to form pentacyclic compounds.
Keywords: phosphorus(III) halides, bridgehead phosphorus atom, condensed heterocyclic systems
containing phosphorus, heterocyclization, phosphorylation.
In recent times we have developed new synthetic routes to phosphorus-containing condensed
heterocyclic systems, which include direct reactions of functionalized aromatic [1, 2] and heteroaromatic [3-8]
compounds with phosphorus(III) halides. We have shown previously that electron-rich substrates [1-6], which
react by an addition-elimination mechanism, and 1,3-azoles [7, 8], which react by the so-called ylide mechanism
[9], can be used in this method.
Derivatives of 4,5-dihydrobenzo[e]imidazo[2,1-c][1,4,2]diazaphosphinine 2a,b have been prepared
recently by the phosphorylation of imidazolyl anilide 1a with phosphorus tribromide and phenylphosphine
dibromide [7]. In continuation of this study we have attempted to involve an aryl residue activated by electron
donating groups in the heterocyclic aromatic system. It is known, for example, that 3-dimethylaminobenzamides
react with phosphorus tribromide and phenylphosphine dibromide to give derivatives of 2,3-dihydro-1H-2,1-
benzazaphosphol-3-one [2].
We have discovered that the reaction of the imidazolyl anilide 1b with phosphorus tribromide in
pyridine in the presence of triethylamine gave, as was the case with 1a, cyclic bromophosphonite 2c, the
phosphorus atom nucleus chemical shift of which was close to that in compound 2a. The structure of compound
1
2c was confirmed by subsequent reactions with morpholine and sulfur and also from the H and 31P NMR
spectra of compound 3a containing pentavalent phosphorus atom. The spectroscopic data for the intermediate
amidophosphonite and for compound 3a are comparable with those for the corresponding model compounds [7]
(Scheme 1).
The intramolecular heterocyclization of bromophosphonite 2c into pentacyclic compound appeared to
be possible only after prolonged heating in pyridine in the presence of triethylamine. The trivalent phosphorus
31
compound formed (δ P 33.0 ppm) was oxidized with elemental sulfur to 4a. The non-equivalence of the two
1
methoxy groups of the aromatic ring in the H NMR spectrum of this compound is one indication of the
annelation of the azaphosphole ring.
__________________________________________________________________________________________
Institute of Organic Chemistry, Ukraine National Academy of Science, Kiev 02056, Ukraine; e-mail:
hetfos@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, 385-389, March 2002.
Original article submitted August 26, 2001.
0009-3122/02/3803-0349$27.00©2002 Plenum Publishing Corporation
349

Scheme 1
N
R
P
N
NMe2
N
A
N
R1
O
R2
R3
N
CF3
H
N
RPHal2
5a,b
O
N
N
R1
R2
R3
R
B
CF3
P
1a–c
N
O
1. ∆
2. S8
CF3
2a–e
R1
N
O
1. HN
2. S8
R3
S
P
N
N
N
S
O
N
N
P
N
R1
O
CF3
4a,b
O
R3
CF3
3a,b
1 a R1 = R3 = H, R2 = Cl; b R1 = R3 = OMe, R2 = H; c R1 = R2 = H, R3 = NMe2;
2 a R = Br, R1 = R3 = H, R2 = Cl; b R = Ph, R1 = R3 = H, R2 = Cl; c R = Br,
R1 = R3 = OMe, R2 = H; d R = Ph, R1 = R2 = H, R3 = NMe2; e R = Cl, R1 = R2 = H,
R3 = NMe2 ; 3, 4 a R1 = R3 = OMe; b R1 = H, R3 = NMe2; 5 a R = Ph; b R = Br
Increase of the electron density in the ortho position to the carbamide group of the aromatic ring by
using the derivative of 3-dimethylaminobenzoic acid 1c caused equalization in the reactivity of the imidazole
and the electron-rich aromatic groups. In this case the reaction with phosphorus tribromide was ambiguous. In
order to estimate quantitatively the reactivity of these two reaction systems (corresponding to heterocyclization
by routes B and A) we carried out the reaction of imidazolyl anilide 1c with phenylphosphine dibromide.
It was established with the help of 31P NMR spectroscopy [2, 7] that when the reaction was carried out
under standard phosphorylation conditions (pyridine/triethylamine) the ratio of the products 2d and 5a,
corresponding to reaction via routes B and A respectively, was about 1.0:0.7. Synthesis of the pentacyclic
compound 4b is probably interfered by the ambiguous conversion of bromophosphonite 5b which is probably
connected with the difficulty of realization of the ylide mechanism [9] at intramolecular phosphorylation of the
imidazole nucleus.
The reaction of compound 1c with a highly reactive phosphorylating agent like phosphorus tribromide
in the pyridine/triethylamine occurred unselectively and gave an unidentified mixture of products. We
considered that heterocyclization of compound 1c would occur regioselectively under milder conditions. The
350

expected result was achieved by using phosphorus trichloride in a less polar solvent (dichloromethane) in the
31
presence of triethylamine. The cyclic chlorophosphonite 2e formed has δ P 42.0 ppm in dichloromethane and
50.2 ppm in pyridine which correlates with the values of δ 31P for the brominated analogs 2a and 2c. Compound
2e was converted into the phosphorus(V) compound 3b by consecutive treatment with morpholine and sulfur.
Addition of sulfur was carried out in pyridine solution in the presence of triethylamine on heating according to
the previously developed method [7]. Spectroscopic data for both the intermediate amidophosphonite and
compound 3b were in agreement with those for the corresponding model compounds [7].
Since PCl3, in contrast to PBr3, did not form cyclic compounds with 3-dimethylaminobenzamides [2],
the nucleophilic iodide ion catalysis was used for the intramolecular heterocyclization of compound 2e in
pyridine solution. The phosphorus(III) pentacyclic compound formed had δ 31P 17.9 ppm and, unlike the
compound with two methoxy groups, added sulfur relatively rapidly to give the phosphorus(V) compound 4b.
The derivatives of the new heterocyclic system benzo[3,4][1,2]azaphospholo[1,2-a]benzo[e]-
imidazolo[2,1-c][1,4,2]diazaphosphinine, 4a,b, prepared in this study are high-melting crystalline substances,
poorly soluble in the common organic solvents. Compounds 4a,b hydrolyzed when heated in wet solvents. The
possibility of selective hydrolysis of these compounds is the object of a further study.
EXPERIMENTAL
All manipulations of air-sensitive substances were carried out in atmosphere of dry argon. 31P and
1H NMR spectra were recorded with a Varian VXR-300 spectrometer (121 and 300 MHz respectively) with
TMS as internal standard (1H) and 85% H3PO4 as external standard (31P). IR spectra in KBr disks were recorded
with an UR-20 instrument.
The imidazolyl anilide starting materials 1b,c were synthesized in an analogous way to compound 1a
[7].
1-(3,5-Dimethoxyphenylcarboxamido)-2-(1H-1-imidazolyl)-5-trifluoromethylbenzene (1b). Yield 93%;
1
mp 180°C (toluene–heptane). IR spectrum (KBr), ν, cm-1: 1680 (C=O), 1590. H NMR spectrum (DMSO-d6),
δ, ppm, J (Hz): 3.79 (6H, s CH3); 6.72 (1H, t, J = 2.4, 4-H, ArCO); 6.98 (2H, d, J =2.4, 2,6-H ArCO); 7.07 (1H,
br.s, imidazole); 7.48 (1H, m, imidazole); 7.74 (1H, d, J = 8.4, 3-H); 7.82 (1H, br. s, J = 8.4, 4-H); 7.97 (1H, s,
imidazole); 8.04 (1H, br. s, 6-H). Found, %: C 57.99, H 3.99, N 11.30. C19H16F3N3O3. Calculated, %: C 58.31,
H 4.12, N 10.74.
1-(3-Dimethylaminophenylcarboxamido)-2-(1H-1-imidazolyl)-5-trifluoromethylbenzene (1c).
Yield 51%; mp 167-168°C (toluene–heptane). IR spectrum (KBr), ν, cm-1: 3300 (N–H), 1650 (C=O), 1590.
1H NMR spectrum (DMSO-d6), δ, ppm, J (Hz): 2.94 (6H, s, NMe2); 6.92 (1H, dd, J = 8.1, 2.4; 6-H ArCO); 7.06
(1H, s, imidazole); 7.08-7.11 (1H, m, 4-H ArCO); 7.11 (1H, s, 2-H ArCO); 7.49 (1H, s, imidazole); 7.73 (1H, d,
J = 8.4, 3-H); 7.80 (1H, dd, J 8.4, 1.8, 4-H); 7.96 (1H, s, imidazole); 8.06 (1H, br. s, 6-H). Found, %: C 61.32;
H 4.53; N 14.65. C19H17F3N4O. Calculated, %: C 60.96; H 4.58; N 14.97.
e
5-(3,5-Dimethoxybenzoyl)-4-morpholino-4-thioxo-7-trifluoromethyl-4,5-dihydrobenzo[ ]imidazo-
c
Phosphorus tribromide (0.4 ml, 4.21 mmol) was added to stirred mixture
[2,1- ][1,4,2]diazaphosphinine (3a).
of imidazolyl anilide 1b (1.65 g, 4.21 mmol) and triethylamine (1.17 ml, 8.40 mmol) in pyridine (20 ml) at
-45°C. The reaction mixture was stirred for 2 h in the cold (-45 to 0°C) and then at 20°C for 20 h. The solution
of bromophosphonite 2c formed in this way (31P NMR spectrum, δ: 45.6 ppm) was cooled below 0°C and then
triethylamine (0.6 ml, 4.30 mmol) was added with stirring, followed by morpholine (0.37 ml, 4.21 mmol), and
then sulfur (160 mg) over 10 min. The reaction mixture was heated for 10 h at 85°C, then cooled to 20°C,
diluted with toluene (30 ml), and filtered. The filtrate was evaporated to dryness in vacuum and methanol (4 ml)
was added to the residue. The crystalline mass which formed was squeezed out on the filter and washed with a
small amount (2-4 ml) of cold methanol. Yield 1.04 g (46%); mp 238-239°C (EtOH–H2O). IR spectrum (KBr),
351

ν, cm-1: 3090 (C–H, arom), 2920 (CH2), 1680 (C=O), 1595. 31P NMR spectrum (CDCl3), δ: 43.9 ppm. 1H NMR
spectrum (CDCl3), δ, ppm, J (Hz): 2.84 (2H, m, NCH2); 3.42 (2H, m, NCH2); 3.67 (2H, m, OCH2); 3.8 (8H,
s + m, 2OCH3 + OCH2); 6.45 (1H, t, J = 2.1, 4-H ArCO); 6.92 (2H, br. s, 2-H ArCO); 7.30 (1H, s, 6-H); 7.49
(1H, m, 2-H); 7.55 (1H, d, J = 9.0, 8-H); 7.61 (1H, d, J = 9.0, 9-H); 7.66 (1H, m, 1-H). Found, %: N 10.45;
P 5.73. C23H22F3N4O4PS. Calculated, %: N 10.40; P 5.75.
a
e
12,14-Dimethoxy-15-thioxo-7-trifluoromethyl-10H-benzo[3,4][1,2]azaphospholo[1,2- ]benzo[ ]-
c
Solution of bromophosphonite was obtained from
imidazo[2,1- ][1,4,2]diazaphosphinin-10-one (4a).
2c
imidazoyl anilide 1b (1.65 g, 4.21 mmol) as described above except that triethylamine (2.0 ml, 14.35 mmol) was
used. The reaction mixture was heated at 85°C for 20 h to give pentacyclic phosphorus(III) compound (31P NMR
spectrum, δ: 33.0 ppm). Sulfur (150 mg) was added to the reaction mixture which was heated for 5 h at 85°C.
The reaction mixture was cooled to 20°C, diluted with toluene (30 ml), and left to crystallize for 12 h. The solid
was filtered off, washed initially with benzene, and then with water and ethanol. Yield 0.61 g (32%);
mp >300°C. IR spectrum (KBr), ν, cm-1: 1725 (C=O), 1600. 31P NMR spectrum (DMSO-d6), δ: 28.5 ppm.
1H NMR spectrum (DMSO-d6), δ, ppm, J (Hz): 3.97 (3H, s, OCH3); 4.10 (3H, s, OCH3); 7.13 (2H, m,
11-H + 13-H); 7.46 (1H, s, 2-H); 8.03 (1H, d, J = 8.7, 6-H); 8.29-8.30 (2H, m, 5-H + 8-H); 8.40 (1H, s 3-H).
Found, %: N 9.46; P 6.72. C19H13F3N3O3PS. Calculated, %: N 9.31; P 6.86.
Phosphorylation of Imidazolyl Anilide 1c with Phenylphosphine Dibromide. Phenylphosphine
dibromide (0.45 ml, 3.15 mmol) was added with stirring at -30°C to solution of imidazolyl anilide 1c (1.18 g,
3.15 mmol), triethylamine (0.88 ml, 6.30 mmol), and pyridine (15 ml). The mixture was stirred in cold (-30°C to
0°C) and then for 20 h at 20°C. 31P NMR spectrum, δ: 4.7 ppm (2d); 50.0 ppm (5).
e
5-(3-Dimethylaminobenzoyl)-4-morpholino-4-thioxo-7-trifluoromethyl-4,5-dihydrobenzo[ ]imidazo-
c
Phosphorus trichloride (0.3 ml, 3.43 mmol) was added with stirring at
[2,1- ][1,4,2]diazaphosphinine (3b).
-15°C to mixture of imidazolyl anilide 1c (1.285 g, 3.43 mmol), triethylamine (1.0 ml, 7.17 mmol) and
methylene chloride (20 ml). The reaction mixture was stirred for 1 h while cooling from -15 to 5°C and was then
stirred for further 20 h at 20°C. After this triethylamine (0.5 ml, 3.59 mmol) and morpholine (0.3 ml, 3.44 mmol)
were added with stirring to the solution of chlorophosphonite 2e formed (31P NMR spectrum, δ: 42.0 ppm) at
0°C. The reaction mixture was stirred at 20°C for 30 min and then evaporated to dryness in vacuum. Sulfur
(130 mg), pyridine (12 ml), and triethylamine (0.2 ml) were added to residue, the mixture was heated at 85°C
for 16 h, cooled to 20°C, diluted with toluene (30 ml), and filtered. The filtrate was evaporated to dryness at
lowered pressure and the residue was dissolved in toluene (40 ml). The solution was extracted with 10% HCl
(50 ml), and the extracted salt was treated with activated charcoal and filtered after 30 min. The base was
obtained by treating the filtrate with aqueous ammonia. The solid was filtered off, washed with water, and dried.
Methanol (3-4 ml) was added to the obtained yellow powder. The crystalline mass formed was squeezed out on
the filter and washed with a small amount of cold aqueous methanol (2-4 ml, MeOH–H2O, 9:1) to give
compound 3b (510 mg, 29%); mp 165-167°C (EtOH–H2O, 3:2). IR spectrum (KBr), ν, cm-1: 3090 (C–H arom);
1
2920, 2870 (CH2); 1680 (C=O); 1595. 31P NMR spectrum (CDCl3), δ: 43.9 ppm. H NMR spectrum (CDCl3),
δ, ppm, J (Hz): 2.83 (2H, m, NCH2); 3.41 (2H, m, NCH2); 3.65 (2H, m, OCH2) 3.78 (2H, m, OCH2); 6.8-6.9
((2H, dd or d + d, 4,6-H ArCO); 7.19 (1H, dd, J = 7.8, 7.8, 5-H ArCO); 7.26 (1H, br. s, 2-H ArCO + CHCl3);
7.31 (1H, br. s, 6-H ArCO); 7.49 (1H, m, 2-H); 7.52 (1H, br. d, J = 9.0, 8-H); 7.59 (1H, d, J = 9.0, 9-H); 7.66
(1H, m, 1-H). Found, %: N 13.38; P 5.71. C23H23F3N5O2PS. Calculated, %: N 13.43; P 5.94.
a
e
12-Dimethylamino-15-thioxo-7-trifluoromethyl-10H-benzo[3,4][1,2]azaphospholo[1,2- ]benzo[ ]-
c
Solution of chlorophosphonite was prepared as
imidazo[1,2- ][1,4,2]diazaphosphinin-10-one (4b).
2e
described above, starting from imidazolyl anilide 1c (1.715 g, 4.58 mmol). The reaction mixture was evaporated
in vacuum. KI (50 mg, calcined for 1 h at 205-210°C) was added to the residue, pyridine (20 ml) and
triethylamine (0.65 ml, 4.66 mmol) were poured in and the reaction mixture was heated for 5 h at 85°C. Sulfur
(170 mg) was added and the mixture was heated for a further 3 h. The reaction mixture was cooled to 20°C and
diluted to twice the volume with toluene. The precipitate was filtered off, washed initially with toluene and then
352

with water and ethanol. Yield 700 mg (35%); mp > 300°C. IR spectrum (KBr), ν, cm-1: 1720 (C=O), 1595.
1
31P NMR spectrum (CF3CO2D), δ: 16.4 ppm (d, J = 12.7 Hz). H NMR spectrum (CF3CO2D), δ, ppm, J (Hz):
3.60 (6H, s, N(CH3)2); 7.88 (1H, s, 11-H); 8.08 (1H, d, J = 8.1, 6-H); 7.46 (1H, s, 2-H). Found, % : N 12.98;
P 7.05. C19H14F3N4OPS. Calculated, %: N 12.90; P 7.13.
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