A facile synthesis of new 1,2-dihydro-2λ5-[1,3]oxazolo[5, 4-d][1,3,2]diazaphosphinine derivatives starting from 2-benzoylamino-3, 3-dichloroacrvlonitrile

Article abstract of DOI:10.1002/hc.20470

Easily accessible 2-benzoylamino-3,3-dichloroacrylonitrile, when treated successively with primary amines, phosphorus pentachloride, sulfur dioxide, and various N- or S-nucleophiles, furnishes the corresponding derivatives of 1,2-dihydro-2λ⁵-[1,3]oxazolo[5,4-d][1,3,2]diazaphosphinine, a novel fused heterocycle. The structure of the compounds obtained is unequivocally confirmed by spectroscopic methods and X-ray diffraction analysis.

Full text of DOI:10.1002/hc.20470

Heteroatom Chemistry
Volume 19, Number 5, 2008
5
A Facile Synthesis of New 1,2-Dihydro-2λ -
[1,3]oxazolo[5,4-d][1,3,2]diazaphosphinine
Derivatives Starting from 2-Benzoylamino-3,
3-dichloroacrylonitrile
Oleg V. Shablykin,1 Andrei A. Gakh,2 Vladimir S. Brovarets,1
Eduard B. Rusanov,3 and Boris S. Drach1
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
Kyiv, Ukraine
2Oak Ridge National Laboratory, Oak Ridge, TN 37831-6242
3Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
Received 3 March 2008; revised 7 April 2008
[11], and 1,3-oxazolo[4,5-d]pyrimidine [14]. In
ABSTRACT: Easily accessible 2-benzoylamino-3,3-
the present study, we suggest a facile method
dichloroacrylonitrile, when treated successively with
of converting the above-mentioned electrophilic
primary amines, phosphorus pentachloride, sulfur
reagents into the derivatives of 1,2-dihydro-2λ5-
dioxide, and various N- or S-nucleophiles, furnishes
[1,3]oxazolo[5,4-d][1,3,2]diazaphosphinine, a novel
the corresponding derivatives of 1,2-dihydro-2λ5-
fused heterocyclic system (Scheme 1 and Table 1).
[1,3]oxazolo[5,4-d][1,3,2]diazaphosphinine, a novel
fused heterocycle. The structure of the compounds
obtained is unequivocally confirmed by spectro-
scopic methods and X-ray diffraction analysis.
ꢀ
C
RESULTS AND DISCUSSION
2008 Wiley Periodicals, Inc. Heteroatom Chem 19:506–
511, 2008; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20470
As found formerly [2], 2-benzoylamino-3,3-
dichloroacrylonitrile
1
treated with strongly
basic amines readily cyclizes to give 5-alkylamino-2-
phenyl-1,3-oxazole-4-carbonitriles 2a, b (Scheme 1).
Here we study, for the first time, the reaction of
compounds 2a, b with phosphorus pentachloride.
It appears that the condensation is most conve-
niently performed at 5–20◦C in benzene with excess
phosphorus pentachloride. The initially formed
phosphorylation products could not be isolated in
the pure state, and they were reacted further with
sulfur dioxide and then with excess methylamine,
benzylamine, pyrrolidine, or morpholine to yield
compounds 7a–g. Similar products 7h–j result
from the reaction of intermediate phosphorylation
INTRODUCTION
Starting
from
2-acylamino-3,3-dichloroacrylo-
nitriles used as polycentric electrophiles, synthetic
routes were previously developed to access various
derivatives of 1,3-oxazole [1–8], 1,3-thiazole [7], im-
idazole [9], pyrazole [10,11], 1,3,4-oxadiazole [12],
1,3,4-thiadiazole [13], pyrazolo[1,5-a]pyrimidine
Correspondence to: Boris S. Drach; e-mail: drach@bpci.kiev.ua.
2008 Wiley Periodicals, Inc.
c
ꢀ
506

Facile Synthesis of New 1,2-Dihydro-2λ5-[1,3]oxazolo[5,4-d][1,3,2]diazaphosphinine Derivatives 507
SCHEME 1
products with mercaptans or thiophenols in the
presence of triethylamine (Table 2).
the heterocycle. The perspective view of molecule
7b and selected geometrical parameters are given in
Fig. 1 and Table 3, respectively. The central bicyclic
N(1–3)O(3)C(1–4) bond system is planar (deviations
The final products of the conversion presented
in Scheme 1 have been structurally determined by
1
IR as well as H and 31P NMR spectra, which cor-
˚
from the least-squares plane do not exceed 0.031 A),
˚
roborate the presence of the characteristic group
and the P(1) atom is 0.174 A above this plane. The
in compounds 7a–j. Since the phospho-
benzene ring C(13–18) is almost planar, whereas the
C(7–12) benzene ring is perpendicular to this plane,
the corresponding dihedral angles being 17.0◦ and
81.8◦. The P(1)N(2)N(3)C(2–4) six-membered cycle
has an envelope conformation; the dihedral angle be-
tween the P(1)N(2)N(3) and N(2)N(3)C(2–4) planes
ryl group is bound to only one residue of a N- or
S-nucleophile, one can assume that the phospho-
rus atom is incorporated into a heterocyclic sys-
tem. X-ray diffraction analysis of compound 7b
has enabled unequivocal structural identification of
Heteroatom Chemistry DOI 10.1002/hc

508 Shablykin et al.
TABLE 1 Physical and Analytical Data of Compounds 7
Analysis (%) Found (Calcd.)
Molecular Formula
Compound mp ( ◦C) Yield (%)a
(Mol. Wt.)
C
H
N
P
S
7a
7b
7c
7d
7e
7f
205–206b
265–266c
231–232c
241–242b
239–240c
234–235b
271–272c
170–171b
229–230c
197–198c
30
44
66
39
56
46
62
29
53
45
C25H24N5O2P (457.5) 65.46 (65.64) 5.31 (5.29) 15.09 (15.31) 6.59 (6.77)
C19H20N5O P (381.4) 59.55 (59.84) 5.37 (5.29) 18.58 (18.36) 8.33 (8.12)
–
–
–
–
–
–
–
C31H28N5O2P (533.6) 69.51 (69.78) 5.50 (5.29) 13.41 (13.13) 5.59 (5.80)
2
C19H24N5O2P (385.4) 59.42 (59.21) 5.97 (6.28) 18.44 (18.17) 8.31 (8.04)
C25H28N5O2P (461.5) 65.35 (65.06) 6.29 (6.12) 15.05 (15.17) 6.52 (6.71)
C19H24N5O4P (417.4) 54.39 (54.67) 6.63 (5.80) 16.55 (16.78) 7.44 (7.42)
C25H28N5O4P (493.5) 61.06 (60.85) 5.91 (5.72) 13.90 (14.19) 6.13 (6.28)
C25H22N3O2PS2 (491.6) 60.88 (61.09) 4.66 (4.51) 8.70 (8.55) 6.14 (6.30) 13.11 (13.05)
C31H26N3O2PS2 (567.7) 65.71 (65.59) 4.45 (4.62) 7.33 (7.40) 5.34 (5.46) 11.24 (11.30)
C31H26N3O2PS2 (567.7) 65.27 (65.59) 4.43 (4.62) 7.31 (7.40) 5.28 (5.46) 11.22 (11.30)
7g
7h
7i
7j
aFor twice-crystallized compounds.
bRecrystallization from benzene.
cRecrystallization from EtOH.
TABLE 2 Spectroscopic Data of Compounds 7
Compound 1H NMR δ (ppm)
13C NMR δ (ppm)
31P NMR δ (ppm)
7a
2.98 (d, J = 7.3 Hz, 3H, CH3), 3.44–3.82 (m, 29.21, 43.51, 45.27, 106.75, 125.83
2H, CH2), 4.43–4.67 (m, 2H, CH2), 5.50 (m, 1H, (×2), 127.14 (×2), 127.40, 127.91,
NH), 7.04–7.95 (m, 15H, 3C6H5), 8.57 (m, 1H, 128.20 (×2), 127.47 (×2), 128.83 (×2),
8.0
NH)
129.75, 129.81 (×2), 130.65, 140.20,
141.34, 151.17, 154.93, 157.93
7b
2.14 (m, 3H, CH3), 2.88 (d, J = 3.5 Hz, 3H, 26.77 (×2), 46.32, 106.43, 124.75 (×2),
CH3 ), 4,73–4,91 (m, 2H, CH2), 4.81 (m, 1H, 126.10, 127.09, 127.96 (×2), 128.06
NH), 7.22–7.82 (m, 10H, 2C6H5), 8.00 (m, 1H, (×2), 128.85 (×2), 129.70, 137.26,
9.7
NH)
150.39, 154.53, 156.57
–
7c
7d
3.50–3.81 (m, 2H, CH2), 4.28–4.76 (m, 4H,
2CH2), 5.62 (m, 1H, NH), 7.09–7.79 (m, 20H,
4C6H5), 8.64 (m, 1H, NH)
8.4
2.2
1.76 (m, 4H, 2CH2), 1.84 (m, 2H, CH2), 1.99
(m, 2H, CH2), 2.96 (m, 4H, 2CH2), 3.21 (d,
J = 7.5 Hz, 3H, CH3), 3.51 (m, 2H, CH2), 4.03
(m, 2H, CH2), 7.52–7.97 (m, 5H, C6H5)
1.63 (m, 4H, 2CH2), 1.89 (m, 2H, CH2), 2.00
(m, 2H, CH2), 2.89 (m, 4H, 2CH2), 3.57 (m, 2H,
CH2), 4.06 (m, 2H, CH2), 4.64–4.92 (m, 2H,
CH2), 7.21–7.85 (m, 10H, 2C6H5)
–
–
–
–
7e
7f
3.5
4.1
3.9
2.92 (m, 4H, 2CH2), 3.27 (d, J = 7.2 Hz, 3H,
CH3), 3.35 (m, 2H, CH2), 3.51 (m, 4H, 2CH2),
3.70 (m, 4H, 2CH2), 4.22–4.76 (m, 2H, CH2),
7.45–7.98 (m, 5H, C6H5)
7g
2.86 (m, 4H, 2CH2), 3.24–3.57 (m, 4H, 2CH2),
3.64–3.98 (m, 6H, 3CH2), 4.22–4.62 (m, 2H,
CH2), 4.66–4.95 (m, 2H, CH2), 7.22–7.85
(m, 10H, 2C6H5)
7h
7i
3.08 (d, J = 7.4 Hz, 3H, CH3), 3.32 (m, 1H,
CH2), 3.75 (m, 1H, CH2), 4.41 (m, 2H, CH2),
6.95–7.97 (m, 15H, 3C6H5)
3.45 (m, 1H, CH2), 3.78 (m, 1H, CH2), 4.43
(m, 2H, CH2), 4.48 (m, 1H, CH2), 4.84 (m, 1H,
CH2), 7.01–7.77 (m, 20H, 4C6H5)
–
–
23.0
23.9
24.0
7j
2.07 (s, 3H, CH3), 2.43 (s, 3H, CH3), 5.09 (m, 20.53, 20.95, 47.77, 114.72, 121.50,
2H, CH2), 7.05–7.87 (m, 18H, 2C6H5, 2C6H4)
121.60, 124.96, 125.73 (×2), 128.07,
128.49 (×2), 128.76 (×2), 129.19 (×2),
129.68 (×2), 130.10 (×2), 131.09,
135.20 (×2), 135.38, 135.46 (×2),
139.89, 140.21, 151.94, 157.15, 170.43
Heteroatom Chemistry DOI 10.1002/hc

Facile Synthesis of New 1,2-Dihydro-2λ5-[1,3]oxazolo[5,4-d][1,3,2]diazaphosphinine Derivatives 509
SCHEME 2
FIGURE 1 Perspective view and labeling scheme for
rylation of various β-enaminonitriles [17–20] and
2-aminobenzonitriles [21] with phosphorus pen-
tachloride or related reagents. This process normally
involves the successive conversions A → B → C → D
shown in Scheme 2.
molecule 7b.
is 11.3◦. The N(2), N(4), and N(5) atoms have a
trigonal–planar bond configuration (the sum of the
bond angles is equal to 359.9◦, 360.0◦, and 358.4◦, re-
spectively). The P(1) atom adopts a significantly dis-
torted tetrahedral coordination geometry. Because
of the nN-π conjugation, the N(4)–C(4) bond is no-
However, compounds 2a, b lack a primary
amino group and hence the initial stage of their
phosphorylation should proceed differently from the
A → B conversion. The latter gives rise to the N P
bond formation, and it may be conjectured, by anal-
ogy, that phosphorylation of a secondary amino
group results in structure 3 bearing the N P bond. At
the same time, one cannot rule out initial phospho-
rylation at the cyano group leading to structure 4,
provided the reaction is performed under very mild
conditions. This phosphorylation pathway was es-
tablished, e.g., for malononitrile and its derivatives
[22]. This is, of course, only indirect evidence that
phosphorylation can initially yield two alternative
˚
tably shortened (1.315(3) A) and is thus outside the
standard range for the N(sp2)–C(sp2) single bonds
˚
(1.43–1.45 A) [15,16].
Thus, the molecular structure has been firmly
established for the whole family of compounds
7. Nevertheless, a detailed mechanism of the cas-
−→
cade conversion 2
At first glance, it would seem that the reactions
concerned represent a particular case of phospho-
7 has yet to be elucidated.
→
◦
˚
TABLE 3 Selected Bond Lengths (A) and Bond Angles ( ) of 7b
Bond Angle ( ◦)
˚
Bond Length (A)
C(1)–N(1)
C(1)–O(3)
C(2)–C(3)
C(2)–N(1)
C(3)–O(3)
C(2)–C(4)
C(3)–N(2)
C(4)–N(3)
N(2)–P(1)
N(3)–P(1)
N(5)–P(1)
O(2)–P(1)
1.291(3)
1.405(3)
1.363(3)
1.392(3)
1.356(2)
1.432(3)
1.343(3)
1.315(3)
1.723(2)
1.617(2)
1.611(2)
1.474(2)
N(1)–C(1)–O(3)
C(3)–O(3)–C(1)
O(3)–C(3)–C(2)
C(3)–C(2)–N(1)
C(3)–C(2)–C(4)
N(1)–C(2)–C(4)
N(2)–C(3)–O(3)
N(2)–C(3)–C(2)
N(3)–C(4)–C(2)
N(3)–P(1)–N(2)
O(2)–P(1)–N(2)
O(2)–P(1)–N(5)
O(2)–P(1)–N(3)
N(5)–P(1)–N(3)
N(5)–P(1)–N(2)
113.5(2)
103.6(2)
108.8(2)
109.0(2)
120.7(2)
130.2(2)
122.6(2)
128.5(2)
120.5(2)
105.4(1)
110.1(1)
110.6(1)
115.6(1)
109.6(1)
105.0(1)
Heteroatom Chemistry DOI 10.1002/hc

510 Shablykin et al.
intermediates, 3 and 4, which are likely to cyclize
readily to the same intermediate 5. The further con-
versions 5 → 6 → 7 appear quite trivial, since pro-
cesses of this kind are widespread.
General Procedure for the Synthesis of
1-Alkyl-2,4-bis[benzylthio(4-methylphenylthio)]-
6-phenyl-1,2-dihydro[1,3]oxazolo[5,4-
d][1,3,2]diazaphosphinin-2-ones 7h–j
To conclude, although formation of intermedi-
ates 3–6 or possibly of some other species has a
conjectural status, this in no way minimizes the
They were obtained similarly to compounds
7a–g using benzylmercaptan (1 mmol) or 4-
methylbenzenethiol (1 mmol) as a nucleophilic
reagent and triethylamine (1.5 mmol) as a base.
preparative importance of the cascade conversion
−→
2
7, which affords the derivatives of a novel
→
fused heterocycle, 1,2-dihydro-2λ5-[1,3]oxazolo[5,4-
d][1,3,2]diazaphosphinine. Moreover, a remarkable
ease of phosphorylation observed for compounds
2a, b suggests the great potentialities of the reac-
tion between various enaminonitriles containing the
characteristic moieties
X-Ray Structure Determination for 7b
Crystal Data. C19H20N5O2P, M = 381.37, mon-
oclinic, space group C2/c (N 15), a = 19.312(3),
◦
˚
b = 6.4046(9), c = 31.583(4) A, β = 102.902(2) ,
3
−3
˚
V = 3807.9(9) A , Z = 8, dc = 1.330 g cm , µ =
0.169 mm−1, F(000) = 1600, crystal size ca. 0.50 ×
0.22 × 0.05 mm3.
and phosphorus pentachloride.
Data Collection. All crystallographic measure-
ments were performed at room temperature on a
Bruker Smart Apex II diffractometer. The cell pa-
rameters were obtained from the least-squares treat-
ment of 1934 reflections in the θ range of 2.16–24.13◦.
The intensity data were collected within the range of
2.16◦ ≤ θ ≤ 26.24◦ using Mo Kα radiation (λ = 0.71078
EXPERIMENTAL
The NMR spectra were recorded on a Varian Gemini
300 spectrometer at 300 (1H), 100.60 (13C), and 80.95
MHz (31P) in DMSO-d6. 1H NMR and 13C NMR chem-
ical shifts are given in δ (ppm) relative to Me4Si as an
internal standard. 31P NMR spectra were recorded
relative to 85% H3PO4 as an external standard. IR
spectra were measured on a corresponding UR-20
spectrometer for KBr disks.
˚
A). The intensities of 7662 reflections were collected
(3763 unique reflections, R = 0.030). Data were
int
corrected for Lorentz and polarization effects.
Structure Solution and Refinement. The struc-
ture was solved by direct methods and refined
by the full-matrix least-squares technique in the
anisotropic approximation for non-hydrogen atoms
using the SHELXS97 and SHELXL97 programs
[23,24]. Hydrogen atoms were located in the dif-
ference Fourier maps and refined isotropically. The
SADABS absorption correction was applied (the ra-
tio of the minimum-to-maximum apparent trans-
mission is 0.533). In the refinement, 3763 reflections
(2507 reflections with I ≥ 2σ(I)) were used. Conver-
gence was obtained at R = 0.0462 and wR = 0.0973,
General Procedure for the Synthesis of
1-Alkyl-2,4-bis[benzylamino(methyl amino,
morpholino,pyrrolidino)]-6-phenyl-1,2-di-
hydro[1,3]oxazolo[5,4-
d][1,3,2]diazaphosphinin-2-ones 7a–g
To a vigorously stirred solution of PCl5 (1.2 mmol)
in C6H6 (15 mL), 2a, b (0.5 mmol) obtained by the
known procedure [2,5] were added at 5◦C. The re-
action mixture was stirred at ambient temperature
for 20 h, saturated with SO2, evaporated under vac-
uum (1 Torr) at 40◦C. The residue was treated with
diethyl ether (5 mL), filtered off, and suspended in
THF (10 mL), followed by adding the correspond-
ing amine (2.5 mmol in THF (5 mL) at 20◦C. The
reaction mixture was stirred for 6 h at 30◦C. Then
it was treated with water (50 mL), filtered, washed
with EtOH and ether, and purified by recrystal-
lization from an appropriate solvent to give 7a–g
(Table 1).
1
2
GOF = 1.028 (324 parameters; obs./var. ratio = 7.74;
the largest and minimal peaks in the final differ-
3
˚
ence map are 0.21 and −0.30 e/A , the weighting
scheme is as follows: ω = 1/[σ2(Fo2) + (0.0436P)2 +
1.5472P], where P = (Fo2 + 2Fc2)/3). Full crystallo-
graphic details have been deposited at Cambridge
Crystallographic Data Centre (CCDC). Any request
to the CCDC for these materials should quote the
full literature citation and reference number CCDC
670139.
Heteroatom Chemistry DOI 10.1002/hc

Facile Synthesis of New 1,2-Dihydro-2λ5-[1,3]oxazolo[5,4-d][1,3,2]diazaphosphinine Derivatives 511
[11] Popil’nichenko, S. V.; Pilyo, S. G.; Brovarets, V. S.;
Chernega, A. N.; Drach, B. S. Zh Obshch Khim 2005,
ACKNOWLEDGMENTS
This research was supported in part by the IPP pro-
gram through the Science and Technology Center in
Ukraine (STCU). A contribution from the Discovery
Chemistry Project (P-199).
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