Synthesis and properties of 4,5-dihydrobenzo[e]imidazo[2,1-c][1,4,2]diazaphosphinine derivatives

Article abstract of DOI:10.1002/hc.10000

A number of 4,5-dihydrobenzo[e]imidazo[2,1-c][1,4,2]diazaphosphinine derivatives were prepared by the direct phosphorylation of 1-(4-Chloro-phenylcarboxamido)-2-(1H-1-imidazolyl)-5-trifluoromethylbenzene in basic medium with phosphorus(III) bromide and dibromophenylphosphine. The amide was reacted with phosphorus(III) bromide to yield the tricyclic compound. The tricyclic compound with a trivalent phosphorus atom went through the diazaphosphine ring opening upon treatment with secondary amines in the presence of sulphur.

Full text of DOI:10.1002/hc.10000

Heteroatom Chemistry
Volume 13, Number 1, 2002
Synthesis and Properties
of 4,5-Dihydrobenzo[e]imidazo[2,1-c]
[1,4,2]diazaphosphinine Derivatives
Vladimir V. Ivanov, Alexandr A. Yurchenko, Alexander N. Chernega,
Alexandr M. Pinchuk, and Andrej A. Tolmachev
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev-94, 02094, Ukraine
Received 10 March 2001; revised 3 July 2001
1,3-Azoles are reacted with phosphorus(III) and
ABSTRACT: A number of 4,5-dihydrobenzo[e]imi-
phosphorus(V) halides to yield the products of
dazo[2,1-c][1,4,2]diazaphosphinine derivatives were
meso-phosphorylation [5]. This reaction was shown
prepared by the direct phosphorylation of 1-(4-Chloro-
to follow the so-called “ylide” mechanism [5b] and
phenylcarboxamido)-2-(1H-1-imidazolyl)-5-trifluoro-
can be formally regarded as a phosphorylation of
methylbenzene in basic medium with phosphorus(III)
the carbon atom with inverse reactivity. Herein, we
bromide and dibromophenylphosphine. The tricyclic
report on the first example of an annelation of a
compounds 6a, 6b, and 9 having a trivalent phos-
phosphorus-containing heterocycle to a 1,3-azole
phorus atom undergo the diazaphosphinine ring
nucleus by the direct phosphorylation with phospho-
opening upon treatment with secondary amines in
rus(III) bromides, which resulted in the construction
of the novel fused heterocyclic system starting from
the amide 4.
C
the presence of sulfur.
2002 John Wiley & Sons, Inc.
Heteroatom Chem 13:84–92, 2002; DOI 10.1002/hc.10000
RESULTS AND DISCUSSION
INTRODUCTION
The synthesis of the starting material was carried
out according to Scheme 1. Imidazole was arylated
with 1-chloro-2-nitro-4-trifluoromethylbenzene (1)
in DMF in the presence of K2CO3. Reduction of the
nitro group in 2 using the Fe/AcOH system afforded
the o-imidazolylaniline (3). Acylation of the latter
with p-chlorobenzoyl chloride in pyridine gave rise
to the amide 4.
The amide 4 was reacted with phosphorus(III)
bromide to yield the tricyclic compound 5 ( 31P =
43.7 ppm in pyridine) (Scheme 2). The reaction
can be carried out in a low-polar solvent (toluene)
in the presence of two equivalents of triethylamine
as well as in the pyridine medium. However, in
the latter case, the reaction appeared to proceed
more smoothly in the presence of triethylamine.
Significantly, this condition, in contrast to the
The direct C-phosphorylation with phosphorus(III)
halides in basic medium has proved to be an effi-
cient and convenient method for the introduction of
a variety of phosphorus functions in the electron-rich
aromatic [1] and heteroaromatic [2] compounds.
When applied to functionalized pyrroles [3] and
pyrazoles [4], this reaction has afforded a number
of novel phosphorus-containing fused heterocycles.
These heterocyclizations inevitably require two nu-
cleophilic centers, one of them being an endocyclic
carbon atom.
Correspondence to: Vladimir V. Ivanov; e-mail: vovch1@yahoo.
com.
c
2002 John Wiley & Sons, Inc.
84

Synthesis and Properties of 4,5-Dihydrobenzo[e]imidazo[2,1-c][1,4,2]diazaphosphinine Derivatives 85
of the compounds 7a–c, as well as other prepared
compounds, are summarized in Table 2.
The structure of 7a was proved by X-ray analy-
sis. The perspective view of molecule 7a is shown
in Fig. 1 [6], selected geometrical parameters be-
ing given in Table 3. The P(1)C(1)N(2)C(4)C(5)N(3)
six-membered central heterocycle has the confor-
mation of a half-boat [7]: the C(1), N(2), C(4),
C(5), and N(3) atoms are roughly coplanar (de-
SCHEME 1
viations from the least-squares plane do not ex-
phosphorylation of N-alkylimidazoles [5b], is not
obligatory. This fact can be explained by decreased
basicity of the imidazole moiety in the amide 4
resulting in increased acidity of the 2-C H bond
in an intermediate imidazolium salt formed by N-
phosphorylation with any of P Br species present
in the reaction mixture. The structure of 5 was con-
˚
ceed 0.13 A), whereas the P(1) atom is out of
˚
this plane by 0.58 A; the “edge” P(1)C(1)N(3)
forms with the “bottom” C(1)N(2)C(4)C(5)N(3) a
dihedral angle of 25 . Torsion angles in this
ring are as follows: P(1) C(1) N(2) C(4) 2.8 ,
C(1) N(2) C(4) C(5) 17.9 , N(2) C(4) C(5) N(3)
2.3 , C(4) C(5) N(3) P(1) 37.0 , C(5) N(3) P(1)
C(1) 42.0 , N(3) P(1) C(1) N(2) 23.2 . The C(1)
N(1)C(2)C(3)N(2) and C(4)–C(9) rings are approxi-
mately coplanar to the best least-squares plane of
the central heterocycle, the corresponding dihedral
angles being only 12.4 and 13.6 . Bond lengths and
angles of 7a are unexceptional [8,9].
1
firmed by 31P and H NMR spectra (Table 1) as well
as by chemical transformations. Compound 5 was
prepared in toluene or pyridine and used in these
reactions without isolation.
The bromine atom in 5 can easily be substituted
by a secondary amino group upon treatment with
the corresponding amine. The resulting cyclic phos-
phamides 6a–c possess 31P values of about 33 ppm
in pyridine solutions. One of these compounds (6a)
was isolated and additionally characterized by its 1H
NMR spectrum (Table 1). The phosphamides 6a–c
as well as the other derivatives of benzo[e]imidazo
[2,1-c][1,4,2]diazaphosphinine having a phospho-
rus(III) atom are air-sensitive compounds. Sulfur
was added to the reaction mixtures in order to con-
vert 6a–c into the air-stable phosphorus(V) deriva-
tives 7a–c. It was found that the sulfur addition takes
place slowly. For example, this reaction in the case
of 6a is complete after 9 h of heating of the reac-
tion mixture at 85 C. However, some acceleration
can be achieved by increasing the basicity of the
reaction medium via addition of triethylamine. This
phenomenon was used in the synthesis of 7c. The
31P NMR, IR, physical, and elemental analysis data
The rotation of the morpholine moiety in 7a
around the P N bond is sterically hindered by the
adjacent acyl substituent. As a consequence, the pro-
tons of four methylene groups in the morpholine ring
1
become diastereotopic and are observed in the H
NMR spectrum as four 2H-multiplets. On the con-
trary, in the 1H NMR spectrum of 8, prepared by hy-
drazinolysis of 7a, these protons are observed as two
4H-multiplets.
FIGURE 1 Perspective view and labeling scheme for
molecule 7a (hydrogen atoms are omitted for clarity).
SCHEME 2

86 Ivanov et al.
TABLE 1 The 1H NMR Data of 5, 6a, 7a–c, 8–10 [ (ppm) and J (Hz) values]
p-ClC H CO
6
4
H-1
H-2
H-6
(d, 1H)
H-8
(dd, 1H)
H-9
(d, 1H)
o-H
(d, 2H)
m-H
(d, 2H)
Solvent
(m, 1H) (m, 1H)
Other Signals
5
CD3CN
7.55
7.01
8.28
7.44
7.69
7.79, 8.4
8.07, 8.4
7.58, 8.1
6.98, 8.4
7.44, 8.1
6.84, 8.4 3.07 (m, 2H, NCH2),
2.96 (m, 2H, NCH2),
6a C6D6
7.67,1.2 7.07, 8.4, 6.73, 8.4
1.2
2.44 (m, 4H, OCH2)
7.61–7.64 7.64–7.66 7.41, 8.7 2.92 (m, 2H, NCH2),
3.41 (m, 2H, NCH2),
7a CDCl3
7.52
7.66
7.69
8.46
7.17
7.56, 9.0
3.67 (m, 2H, OCH2),
3.81 (m, 2H, OCH2)
7.46, 8.4 1.42 (m, 2H, CH2),
1.53(m, 2H, CH2),
1.64 (m, 2H, CH2),
3.03 (m, 2H, NCH2),
3.27 (m, 2H, NCH2)
7.35, 8.8 1.18 (t, J =7.2 Hz, 6H,
CH3), 3.16 (m, 2H,
NCH2), 3.45 (m, 2H,
NCH2)
7b DMSO-d6
7c CDCl3
7.36
7.72, 8.7
8.17, 8.7
7.65, 8.4
7.52
7.68
7.06
7.49–7.52 7.60, 8.1
7.56, 8.8
8
9
DMSO-d6
C6D6
7.53
7.11
7.45
8.43
7.73
8.36
7.54
7.40
7.47
7.44, 8.7
8.13, 8.7
3.18 (m, 4H, NCH2),
3.54 (m, 4H, OCH2),
9.43 (s, 1H, NH)
6.84–6.88 7.08–7.12 7.12–7.15 6.83, 8.7 6.49 (m, 1H, p-H Ph),
6.73 (m, 2H, o-H Ph),
6.97 (m, 2H, m-H Ph)
7.39, 8.7 7.53 (dt, 7.5 Hz,
4.2 Hz, 2H, m-H Ph),
10
acetone-d6
7.80, 8.4
8.24, 8.4
7.69, 8.7
7.65 (m, 1H, p-H Ph),
8.11 (dd, JP,H = 16.5,
7.2 Hz, 1H, o-H Ph)
TABLE 2 The Data of 7a–c, 8, 10, 12a–e
Found% (Calcd %)
Yield
(%)
31
P (ppm), solvent
-1
mp ( C)
Formula
N
P
IR (KBr, cm
)
7a
59
193–194a C21H17ClF3N4O2
PS 1/2 C4H8O2
45.1, CD3CN
10.32 (10.06) 5.38 (5.56) 1700 (C O)
7b
7c
8
48
61
86
32
53
12
32
50
59
220–221b C22H19ClF3N4OPS
218–219b C21H19ClF3N4OPS
269–270c C14H14F3N4OPS
212–215d C23H14ClF3N3OPS
45.0, DMSO-d6
45.7, CDCl3
38.8, DMSO-d6
40.4, acetone-d6
11.08 (10.97) 5.78 (6.06) 1695 (C O)
11.32 (11.23) 6.15 (6.21) 1677 (C O)
15.27 (14.97) 8.61 (8.27) 3750 (NH), 1630, 1610
8.44 (8.34) 6.86 (6.15) 1690 (C O)
11.23 (11.67) 5.04 (5.16) 3450 (NH), 1690 (C O)
11.95 (11.75) 5.16 (5.20) 3415 (NH), 1698 (C O)
11.88 (11.71) 5.11 (5.18) 3425 (NH), 1700 (C O)
10
12a
12b
12c
12d
12e
189b
C25H26ClF3N5O3PS 55.0, CD3CN
148–149e C27H30ClF3N5OPS
55.8, acetone-d6
153–154e C26H28ClF3N5O2PS 55.4, acetone-d6
163–164b C27H23ClF3N4O2PS 50.4 (m), DMSO-d6
9.38 (9.48)
9.52 (9.51)
5.09 (5.24) 3290 (NH), 1698 (C O)
5.39 (5.26) 3455 (NH), 1700 (C O)
146–147e C28H25ClF3N4OPS
50.2 (m), DMSO-d6
aRecrystallized from i -PrOH. Analytical sample was prepared as dioxanate (7a/dioxane 2:1) by slow evaporation of the dioxane solution upon
standing.
bRecrystallized from a toluene–heptane mixture.
cRecrystallized from EtOH/H2O (1:1).
dRecrystallized from toluene.
eRecrystallized from heptane.

Synthesis and Properties of 4,5-Dihydrobenzo[e]imidazo[2,1-c][1,4,2]diazaphosphinine Derivatives 87
˚
Sulfur addition to 9 afforded the air-stable com-
pound 10. This reaction occurs as slowly as in case
of the phosphamides 6a–c.
TABLE 3 Selected Bond Lengths Aand Angles (deg) in 7a
Bond lengths
S(1) P(1)
P(1) N(3)
P(1) N(4)
P(1) C(1)
O(1) C(11)
N(1) C(1)
N(1) C(2)
N(2) C(1)
N(2) C(3)
N(2) C(4)
N(3) C(5)
N(3) C(11)
C(2) C(3)
C(11) C(12)
Bond angles
1.918(2)
1.736(4)
1.622(4)
1.799(4)
1.205(5)
1.316(5)
1.370(6)
1.375(5)
1.391(5)
1.412(5)
1.437(5)
1.421(5)
1.348(6)
1.493(6)
Sulfur addition to 6a in the presence of mor-
pholine in the reaction mixture gave a product
of the oxidative endocyclic P N bond cleavage
(12a, Scheme 4, Table 4). It was deduced that
the P N bond cleavage occurs in the phospho-
rus(III) derivative 6a because 7a does not react
with morpholine either in pyridine solution or un-
der reflux in MeCN. Morpholine addition to a pyri-
dine solution of 6a resulted in emergence in the
31P NMR spectrum of a signal at = 72.5 ppm.
This signal can be attributed to 11a since its
value is close to that (75.7 ppm) of 1-methyl-1H-2-
imidazolyl(dimorpholino)phosphane [5b]. The reso-
nance peak of 11a has a static low intensity. Thus, an
equilibrium between 6a and 11a probably exists. The
phosphorus atom of 11a is more nucleophilic than
that of 6a because it is no longer in conjugation with
the heterocyclic system. This explains the relative
swiftness of the described transformation, in which
sulfur preferably reacts with 11a to shift the equi-
librium toward the opening of the diazaphosphinine
ring.
The competing process of sulfur addition to 6 be-
came significant when an analogous transformation
of 6b in the presence of piperidine was attempted
and dominated in the case of the reaction of 6c with
Et2NH that did not allow preparation of 12c. The ob-
served increase in the percentage in the formation of
the phosphorus(V) derivatives of type 7 is probably
connected with the growth of basicity of the amine
precursors as well as by the earlier found acceler-
ation of sulfur addition by increasing the medium
basicity.
S(1) P(1) N(3)
S(1) P(1) N(4)
N(3) P(1) N(4)
S(1) P(1) C(1)
N(3) P(1) C(1)
N(4) P(1) C(1)
C(1) N(1) C(2)
C(1) N(2) C(3)
C(1) N(2) C(4)
P(1) N(3) C(5)
P(1) C(1) N(2)
N(1) C(1) N(2)
N(1) C(2) C(3)
N(2) C(3) C(2)
N(3) C(5) C(4)
N(2) C(4) C(5)
116.00(15)
115.89(16)
106.41(19)
116.72(16)
95.61(19)
103.7(2)
104.9(3)
106.3(3)
125.5(3)
121.4(3)
122.5(3)
111.7(4)
112.0(3)
105.1(4)
120.7(4)
119.4(3)
The amide 4 was treated with PhPBr2 to fur-
nish the tricyclic compound 9 ( 31P = 5.5 ppm
in pyridine) (Scheme 3). Again, as in the case of
PBr3, the reaction can be carried out in pyridine
as well as in toluene in the presence of triethy-
lamine. The structure of 9 was also confirmed by
1H NMR spectroscopy and by chemical transfor-
mations. Compound 9 was prepared in toluene or
pyridine and used in these reactions without isola-
tion. 31P NMR-monitoring of the reaction mixture
revealed the formation of an intermediate, = 110.7
ppm, which is probably a product of the amide func-
tion phosphorylation.
The property of the phosphamide 6a to undergo
the diazaphosphinine ring opening upon treatment
with a secondary amine enables the synthesis of the
mixed amide 12c. This transformation can also be
carried out as the treatment of the phosphamide 6b
SCHEME 3
SCHEME 4

88 Ivanov et al.
TABLE 4 The 1H NMR Data of 12a–e [ (ppm) and J (Hz) values]
Imidazole
H-4 H-5
Arene
H-4
p-ClC H CO
6 4
H-6
H-3
(d, 1H)
o-H
m-H
(d, 2H)
Solvent
12a CDCl3
(m, 1H) (m, 1H)
(d, 1H) (dd, 1H)
(d, 2H)
Other Signals
7.32
7.08
8.37, 1.6 7.58, 8.7, 7.34, 8.7 7.67, 8.4 7.40, 8.4 8.27 (bs, 1H, CONH);
1.6 3.76 (m, 4H, OCH2); 3.57
(m, 4H, OCH2); 3.26 (m,
4H, NCH2); 3.04 (m, 4H,
NCH2)
12b acetone-d6
12c acetone-d6
7.73
7.73
7.34
7.35
7.44
7.48
7.72–7.78 8.55, 6.9 7.76, 8.4 7.55, 8.4 8.59 (s, 1H, CONH); 3.09
(bs, 8H, NCH2); 1.54 (m,
12H, CH2)
7.72–7.75 8.53–8.55 7.72–7.75 7.54, 8.7 8.53–8.55 (bs, 1H, CONH);
3.60 (bs, 4H, OCH2); 3.08
(bs, 8H, NCH2); 1.51 (m,
6H, CH2)
12d DMSO-d6
7.67
7.38
8.14
9.65 (s, 1H, CONH); 7.81,
7.62, 7.61, 7.56, 7.46 (bs,
11H, the other aromatic
protons); 3.39 (bs, 4H,
OCH2); 3.02 (bs, 2H,
NCH2); 2.86 (m, 2H,
NCH2)
12e DMSO-d6
7.63
7.35
8.16
9.57 (s, 1H, CONH); 7.82,
7.56, 7.45, (bs, 11H, the
other aromatic protons);
2.96 (m, 2H, NCH2); 2.78
(m, 2H, NCH2); 1.39 (m,
2H, CH2); 1.27 (m, 2H,
CH2)
On the other hand, the 31P NMR spectrum of 12d in
DMSO-d6 solution showed a narrow ( 1 ppm) multi-
plet at = 50.4 ppm. Although the 1H NMR spectrum
is structurally unresolved, some assignments can still
be made (Table 4). Compound 12e was prepared
analogously when 9 was treated with piperidine in
the presence of sulfur. The 31P NMR spectrum of 12e
in CDCl3 solution exhibits two peaks at = 49.06 and
49.60 ppm in 2:1 ratio, whereas in DMSO-d6, a nar-
row multiplet is observed at = 49.7 ppm.
with morpholine in the presence of sulfur. However,
in this case, the greater affinity of 6b for sulfur leads
to a far inferior yield of 12c.
Similarly, addition of morpholine to the pyri-
dine solution of the phenylphosphine 9 gave an
equilibrium mixture of the starting 9 and the prod-
uct of the diazaphosphinine ring cleavage (11d,
31P = 36.9 ppm). The equilibrium is shifted toward
the formation of the cleaved product upon addition
of sulfur. The composition of thus prepared phos-
phorus(V) derivative 12d was confirmed by elemen-
tal analysis. The 31P NMR spectrum of 12d (CDCl3)
exhibited two peaks at = 48.98 and 49.50 ppm (in
EXPERIMENTAL
1
3:1 ratio), which account for the complicated H
NMR spectrum in the same solvent. The occurrence
of 12d in two spectroscopically detected isomers pro-
vides evidence for the presence of a second (after the
asymmetric phosphorus atom) chiral element in the
molecule of this compound. Such an element might
be the axis running through the CArene NImidazole bond.
This chiral axis originates from the hindered rota-
tion around the above-mentioned bond in view of
the steric obstacles caused by the bulky substituents
(NHCOAr and P(S)PhNR2) and/or dipole–dipole in-
tramolecular interactions between the same groups.
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, 1 H, and 13C NMR spectra were obtained
on a Varian VXR-300 spectrometer (121, 300, and
75 MHz, respectively). Chemical shifts are reported
relative to internal tetramethylsilane (1H, 13C) or
external 85% H3PO4 (31P).

Synthesis and Properties of 4,5-Dihydrobenzo[e]imidazo[2,1-c][1,4,2]diazaphosphinine Derivatives 89
filtered and the filtrate was basified with aqueous
K2CO3. The crystalline solid was filtered off and thor-
oughly washed with water to afford 193 g (75%) of
X-ray Structure Determination of 7a
Crystal data: C21H17ClF3N4O2PS 1/2C4H8O2, MW =
˚
˚
556.93 monoclinic, a = 13.984(9) A, b= 10.563(9) A,
1
the pure product. mp = 82–83 C (cyclohexane). H
3
˚
˚
c= 17.358(9) A, = 98.70(5) , V = 2534.5 A , Z = 4,
NMR (DMSO-d6): (ppm) 7.15 (s, 1H, H-5 imida-
zole), 7.50 (s, 1H, H-4 imidazole), 7.98 (d, J = 8.4
Hz, 1H, H-6), 8.01 (s, 1H, H-2 imidazole), 8.30 (dd,
J = 8.4 Hz and 2.0 Hz, 1H, H-5), 8.60 (d, J = 2.0 Hz,
1H, H-3). IR (KBr): 3140, 3030, 1640, 1590, 1555,
1
1
d = 1.46 g cm , space group P21/a, = 3.43 cm ,
F(000) = 1146, crystal size ca. 0.16 mm 0.28 mm
0.38 mm. All crystallographic measurements were
performed at 18 C on a CAD-4-Enraf-Nonius diffrac-
tometer operating in the ω–2 scan mode (the
ratio of the scanning rates ω/2 = 1.2). Intensity
data were collected within the range 2 < < 23
(0 < h< 12, 0 < k< 11, 19 <l < 19) using graphite
1
1525, 1490, 1350 cm . Anal. Calcd. for C10H6F3N3O2:
C, 46.70; H, 2.35; N, 16.34; Found: C, 46.80; H, 2.45;
N, 16.29%.
˚
monochromated Mo K␣ radiation ( = 0.71069 A).
2-(1H-1-Imidazolyl)-5-trifluoromethylaniline(3)
Intensities of 3622 reflections (3241 unique reflec-
tion, R= 0.032) were measured. Data were corrected
for Lorentz and polarization effects, and an empiri-
cal absorption correction based on azimuthal scan
data [10] was applied. The structure was solved
by direct methods and refined by the full-matrix
least-squares technique in the anisotropic approxi-
mation using the CRYSTALS program package [11].
In the refinement, 2046 reflections with I > 3 (I)
were used. Most (ca. 80%) hydrogen atoms were lo-
cated in the different Fourier maps, and the remain-
ing H atoms were placed in calculated positions.
All H atoms were included in the final refinement
with fixed positional and thermal parameters. Con-
vergence was obtained at R= 0.043 and Rw = 0.045,
GOF = 1.107 (352 refined parameters; obs/variabl.
A mixture of the nitro compound 2 (15 g, 58.3 mmol),
Fe powder (30 g, 0.537 mol), HOAc (100 ml), and
i-PrOH (50 ml) was heated in a 0.5-l round bottom
flask equipped with a cooler until a vigorous reac-
tion took place. Then, the heating bath was removed
and the mixture was allowed to boil. When boiling
ceased, the reaction mixture was refluxed for 1.5 h,
cooled to room temperature, and filtered under an at-
mosphere of argon. The filtrate was evaporated un-
der reduced pressure. The dark-brown oily residue
was dissolved in 200 ml of ethanol and treated with
saturated aqueous K2CO3 under vigorous shaking to
provide a clear solution with a Fe-containing lower
layer. The solution was decanted and evaporated un-
der reduced pressure to dryness. The solid residue
was dissolved in dilute HCl. The resulting solution
was treated with charcoal and stirred for 0.5 h, fil-
tered, and basified with aqueous K2CO3. The crys-
talline solid was collected by filtration and washed
with water to afford 8.3 g (63%) of the product. mp =
132 C (toluene–heptane). 1H NMR (CDCl3): (ppm)
3.99 (s, 1H, NH2), 7.06 (d, J = 8.1 Hz, 1H, H-4), 7.09
(s, 1H, H-5 imidazole), 7.15 (s, 1H, H-2), 7.23 (d,
J = 8.1 Hz, 1H, H-5), 7.27 (s, 1H, H-4 imidazole),
7.66 (s, 1H, H-2 imidazole). IR (KBr): 3390, 3228,
5.8; the largest and minimal peaks in the final dif-
3
˚
ference map, 0.26 and 0.33 e/A ). The Chebushev
weighting scheme [12] with parameters 0.70, 0.09,
0.56, 0.02, and 0.17 was used.
Full crystallographic details have been deposited
at the Cambridge Crystallographic Data Centre
(CCDC). Any request to the CCDC for this material
should quote the full literature citation and the
reference number CCDC 157270.
1
3170, 3133, 1650, 1540, 1495, 1456 cm . Anal. Calcd.
for C10H8F3N3: C, 52.87; H, 3.55; N, 18.50; Found: C,
52.87; H, 3.72; N, 18.47%.
1-(2-Nitro-4-trifluoromethylphenyl)-1H-imida-
zole (2)
To a solution of imidazole (75 g, 1.1 mol) in DMF
(140 ml) was added 1-chloro-2-nitro-4-trifluoro-
methylbenzene (1) (150 ml, 1.0 mol). The reaction
mixture was heated to 100–105 C and freshly cal-
cined, finely ground K2CO3(235 g, 1.7 mol) was
added portionwise under stirring. Then the reaction
mixture was stirred at 105–110 C for 1.5 h, cooled to
room temperature, and poured into water (1.8 l). The
precipitated crystalline solid was filtered off, washed
with water, and dissolved in 0.5 l of 10% HCl. The
resulting solution was treated with activated char-
coal (30 g) and stirred for 40 min. The mixture was
1-(4-Chlorophenylcarboxamido)-2-(1H-
1-imidazolyl)-5-trifluoromethylbenzene (4)
4-ClC6H4COCl (5.12 ml, 40.3 mmol) was poured
into pyridine (150 ml). The aniline 3 (9.15 g,
40.3 mmol) was added to the stirred mixture at
15, . . . , 10 C. Stirring was continued for 0.5 h at
5, . . . ,0 C and then for a further 3 h at room tem-
perature. The reaction mixture was poured into wa-
ter (1.7 l). The formed crystalline solid was filtered
off and washed with water to afford 11.6–11.9 g

90 Ivanov et al.
as described for 5. Yield 80%. 31P NMR (benzene):
= 32.7 ppm.
(79–81%) of the product, which was recrystallized
from either toluene or ethanol–water. mp = 201–
202 C (toluene). 1H NMR (DMSO-d6):
(ppm)
7.05 (s, 1H, H-5 imidazole), 7.48 (s, 1H, H-4
imidazole), 7.61 (d, J = 8.4 Hz, 2H, m-H COC6H4Cl),
7.75 (d, J = 8.4 Hz, 1H, H-4), 7.83 (d, J = 8.4 Hz,
1H, H-5), 7.86 (d, J = 8.4 Hz, o-H COC6H4Cl), 7.97
(s, 1H, H-2 imidazole), 8.03 (s, 1H, H-2). IR (KBr):
3355, 3144, 3054, 1667, 1630, 1602, 1549, 1510, 1486,
5-(4-Chlorobenzoyl)-4-morpholino-4-thioxo-7-
trifluoromethyl-4,5-dihydrobenzo[e]imidazo[2,
1-c][1,4,2]diazaphosphinine(7a) and 5-(4-Chlo-
robenzoyl)-4-piperidino-4-thioxo-7-trifluorome-
thyl-4,5-dihydrobenzo[e]imidazo[2,1-c][1,4,2]
diazaphosphinine (7b)
1
1443 cm . Anal. Calcd. for C17H11ClF3N3O: Cl, 9.69;
N, 11.49; Found: Cl, 9.67; N, 11.38%.
To a pyridine solution of 5, prepared as described
above and cooled below 0 C, were added Et3N (0.6
ml, 4.3 mmol) and the corresponding secondary
amine (4.1 mmol). Sulfur (140 mg, 4.4 mmol) was
added to the reaction mixture after 30 min of stir-
ring. Stirring was continued at 85 C for 9 h in the
case of 7a and for 5 h in the case of 7b. The reaction
mixture was cooled to room temperature and diluted
with benzene (20 ml). The precipitate of the salts was
filtered off and the filtrate was evaporated to dryness
under reduced pressure. The residue was triturated
with toluene to give the crystalline solid in the case
of 7a and subjected to flash chromatography on sil-
ica gel using toluene/CH2Cl2 (1:1) as eluent followed
by trituration of the product with hexane in the case
of 7b.
5-(4-Chlorobenzoyl)-4-bromo-7-trifluoromethyl-
4,5-dihydrobenzo[e]imidazo[2,1-c][1,4,2]diaza-
phosphinine (5)
(a) Isolation Method. Phosphorus tribromide
(1.0 ml, 10.5 mmol) was added to a stirred mixture of
4 (3.85 g, 10.5 mmol), Et3N (2.94 ml, 21.1 mmol), and
toluene (60 ml) at 20 C. The mixture was stirred
for 1 h on a cooling bath, the temperature being al-
lowed to rise to 0 C, and then kept overnight at room
temperature. The reaction mixture was filtered, the
filtrate evaporated to half of its initial volume under
reduced pressure and diluted with heptane (20 ml),
then again filtered and the filtrate evaporated almost
to dryness. The residue was repeatedly treated with
heptane to yield the crystalline solid, which was fil-
tered off and dried in vacuum. Yield 67%. 31P NMR
(CD3CN): = 31.5 ppm.
5-(4-Chlorobenzoyl)-4-diethylamino-4-thioxo-7-
trifluoromethyl-4,5-dihydrobenzo[e]imidazo[2,1-
c][1,4,2]diazaphosphinine (7c)
(b) Preparation of the Pyridine Solution of 5.
Phosphorus tribromide (0.39 ml, 4.1 mmol) was
added to a stirred mixture of 4 (1.5 g, 4.1 mmol), tri-
ethylamine (1.2 ml, 8.6 mmol), and pyridine (20 ml)
at 30 C. The mixture was stirred for 1.5 h on a cool-
ing bath, the temperature being allowed to rise to
5 C. The reaction was complete within 1.5 h of stir-
To a pyridine solution of 5, preliminarily cooled be-
low 0 C, were added Et3N (0.6 ml, 4.3 mmol) and
Et2NH (4.1 mmol). Sulfur (140 mg, 4.4 mmol) was
added to the reaction mixture after 30 min of stirring.
Stirring was continued until the sulfur was com-
pletely dissolved, and then the reaction mixture was
left for 3 days at room temperature and treated with
Et3N (1.14 ml, 8.2 mmol) to complete the reaction
in a further 2 days. The reaction mixture was diluted
with benzene (20 ml). The precipitate of the salts was
filtered off and the filtrate was evaporated to dryness
under reduced pressure. The residue was subjected
to flash chromatography on silica gel using toluene
as eluent.
ring of the reaction mixture at room temperature. 31
P
NMR: = 43.7 ppm.
5-(4-Chlorobenzoyl)-4-morpholino-7-trifluoro-
methyl-4,5-dihydrobenzo[e]imidazo[2,1-c][1,
4,2]diazaphosphinine (6a)
To a stirred mixture of 4 (3.85 g, 10.5 mmol), Et3N
(2.94 ml, 21.1 mmol), and toluene (60 ml) was
added phosphorus tribromide (1.0 ml, 10.5 mmol)
at 20 C. The mixture was stirred for 1 h on a
cooling bath, the temperature being allowed to rise
to 0 C, and then kept overnight at room tempera-
ture. To the stirred reaction mixture was added Et3N
(1.5 ml, 10.8 mmol) and morpholine (0.92 ml, 10.5
mmol) at 10, . . . ,0 C. After 4 h of stirring at room
temperature, the reaction mixture was worked-up
4-Morpholino-4-thioxo-7-trifluoromethyl-4,5-di-
hydrobenzo[e]imidazo[2,1-c][1,4,2]diazaphos-
phinine (8)
A solution of the phosphamide 7a (0.5 g, 0.97 mmol)
and N2H4 H2O (0.1 ml, 2.1 mmol) in n-BuOH was
refluxed for 8 h. The reaction mixture was evaporated
under reduced pressure to dryness. The residue was
recrystallized from a EtOH/H2O mixture (1:1).

Synthesis and Properties of 4,5-Dihydrobenzo[e]imidazo[2,1-c][1,4,2]diazaphosphinine Derivatives 91
5-(4-Chlorobenzoyl)-4-phenyl-7-trifluoromethyl-
4,5-dihydrobenzo[e]imidazo[2,1-c][1,4,2]diaza-
phosphinine (9)
4-Chloro-N-[2-{2-[4-morpholinyl(1-piperidinyl)
phosphothioyl]-1H-imidazol-1-yl}-5-(trifluoro-
methyl)phenyl]benzamide (12c)
(a) Isolation Method. To a stirred mixture of
4 (3 g, 8.2 mmol), Et3N (2.4 ml, 17.2 mmol), and
toluene (45 ml) was added PhPBr2 (1.17 ml, 8.2
mmol) at 20 C. The reaction mixture was stirred
for 1 h on a cooling bath, the temperature being
allowed to rise to 0 C, and then kept overnight at
room temperature. The workup procedure was as de-
scribed above for 5. Yield 75%. 31P NMR (toluene):
= 5.5 ppm.
To a pyridine solution of 5, preliminarily cooled be-
low 0 C, were added Et3N (0.6 ml, 4.3 mmol) and
morpholine (4.1 mmol). After having been stirred for
40 min at room temperature, the mixture was treated
with piperidine (4.5 mmol) and sulfur (140 mg,
4.4 mmol), stirred overnight, and diluted with ben-
zene (20 ml). The precipitate of the salts was filtered
off and the filtrate was evaporated to dryness under
reduced pressure. The residue was subjected to flash
chromatography on silica gel using toluene as eluent.
The product was purified by recrystallization from
heptane.
(b) Preparation of the Pyridine Solution of 9. To
a stirred solution of 4 (1.53 g, 4.2 mmol) in pyri-
dine (20 ml) was added PhPBr2(0.6 ml, 4.2 mmol) at
20 C. The reaction mixture was stirred for 1 h on a
cooling bath, the temperature being allowed to rise
to 0 C, and then kept overnight at room temperature.
31P NMR: = 5.4 ppm.
4-Chloro-N-[2-{2-[4-morpholinyl(phenyl)phosp-
hothioyl]-1H-imidazol-1-yl}-5-(trifluoromethyl)
phenyl]benzamide (12d) and 4-Chloro-N-[2-{2-
[1-piperidinyl(phenyl)phosphothioyl]-1H-imid-
azol-1-yl}-5-(trifluoromethyl)phenyl]benzamide
(12e)
5-(4-Chlorobenzoyl)-4-phenyl-4-thioxo-7-trifluo-
romethyl-4,5-dihydrobenzo[e]imidazo[2,1-c][1,
4,2]diazaphosphinine (10)
To a pyridine solution of 9 were added the corre-
sponding amine (16.8 mmol) and sulfur (140 mg,
4.4 mmol). The reaction mixture was stirred
overnight at room temperature, diluted with benzene
(20 ml), and filtered. The filtrate was evaporated to
dryness under reduced pressure. The products were
extracted with heptane.
To the stirred solution of 9 in pyridine was added
sulfur (140 mg, 4.4 mmol) and the reaction mix-
ture was stirred at 110 C for 10 h, cooled to room
temperature, and diluted with benzene (20 ml). The
precipitate of the salts was filtered off and the fil-
trate was evaporated under reduced pressure. The
residue was triturated with toluene (10 ml). The
crystalline solid was filtered off and washed with
toluene.
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