Synthesis of phosphorus-containing barbiturates by the N-arylation of P-zwitterions with 2,4,6-trinitrofluorobenzene

Article abstract of DOI:10.1016/j.mencom.2010.09.013

Barbiturates containing a phosphonium and an N-2,4,6-trinitrophenyl groups were synthesized by the reactions of P-zwitterions with 2,4,6-trinitro-1- fluorobenzene.

Full text of DOI:10.1016/j.mencom.2010.09.013

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 277–278
Synthesis of phosphorus-containing barbiturates by the
N-arylation of P-zwitterions with 2,4,6-trinitrofluorobenzene
Yuri G. Gololobov,* Nikolai V. Slepchenkov, Alexander S. Peregudov and Zoya A. Starikova
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: Yugol@ineos.ac.ru
DOI: 10.1016/j.mencom.2010.09.013
Barbiturates containing a phosphonium and an N-2,4,6-trinitrophenyl groups were synthesized by the reactions of P-zwitterions
with 2,4,6-trinitro-1-fluorobenzene.
Barbiturates are important medical preparations; however, com-
pounds of such a series comprising phosphorus-containing func-
tional groups have been described only by solitary examples,1–3
and barbiturates having nitro groups in N-aromatic rings remained
unknown.
In continuation of studying the reactivity of phosphorus-
containing zwitterions with respect to polynitrohalobenzenes,4–8
we reacted cyano carbanions 1 with 2,4,6-trinitro-1-fluoro-
benzene (TNFB). Judging from changes in the composition of
the reaction mixture with time (monitoring by 19F and 31P NMR
spectroscopy), the process A (Scheme 1) was multi-step through
apparently the formation of σF complex 2. As the result, sub-
stituted barbiturates 3 and ethyl fluoride were obtained.
The reaction proceeded in a methylene chloride solution at
room temperature for two weeks (according to 31P NMR spectro-
scopy). The formation of a fluorinated compound having a
chemical shift at –211 ppm was recorded in the 19F NMR
spectrum; this chemical shift was consistent with that published
for ethyl fluoride. After completion of the reaction, mixture was
kept in an open vessel, the above signal was not found in the
spectrum of the solution, obviously, because of the evaporation
of low-boiling ethyl fluoride. The removal of the solvent and
crystallization of the residue from ethyl acetate gave orange
crystalline compounds 3a,b in 50–60% yields. The composition
and structures of the compounds were determined using ele-
mental analysis, IR and NMR (1H, 13C, 19F, 31P) spectroscopy†
and X-ray diffraction analysis (for 3b) (Figure 1).‡
N
Most likely, the better steric availability of the nitrogen atom
than the carbon atom in the cyano group of zwitterion 1 toward
the attack of TNFB is the main reason behind such an unusual
behaviour. Two ortho-nitro groups in TNFB also create addi-
C
O2N
Alk3P
+
F
NO2
O
O
Ar
N
O2N
†
A solution of 2,4,6-trinitrofluorobenzene (0.5 mmol) in CH2Cl2 (15 ml)
EtO
TNFB
was added dropwise to zwitterion 1 (0.5 mmol) in CH2Cl2 (15 ml). The
solution was kept in a closed vessel at room temperature for two weeks.
Then, the solvent was removed and the residue was crystallized from
ethyl acetate to give compounds 3a and 3b in 52 and 62% yields,
respectively.
1
O2N
1-Phenyl-3-(2,4,6-trinitro)phenyl-5-triisopropylphosphoniomethyl bar-
biturate 3a: mp 249–250 °C. IR (KBr, n/cm–1): 1345, 1542 (NO2), 1643,
1696 (C=O). 31P NMR, d: 41.5. 1H NMR (400 MHz, DMSO-d6) d: 1.35
(dd, 18H, MeCH, JHH 7.2 Hz, JHP 8.0 Hz), 2.74 (m, 3H, MeCH), 3.20
(d, 2H, PCH2, JHP 10.3 Hz), 7.07 (d, 2H, o-H, JHH 7.2 Hz), 7.36 (t, 1H,
p-H, JHH 7.0 Hz), 7.44 (t, 2H, m-H, JHH 7.0 Hz), 9.07 (s, 2H, m-H).
13C NMR (100.61 MHz, DMSO-d6) d: 14.34 (d, CH2P, JCP 46 Hz),
16.85 (MeCH), 21.24 (CHMe, JCP 39 Hz), 74.84 (C–), 124.23 (CHCNO2),
128.05 (o-CH), 128.06 (p-CH), 129.57 (m-CH), 130.32 (CNC=O),
136.86 (NCCNO2), 146.38 (p-CNO2), 148.15 (o-CNO2), 150.44 [NC(O)N],
159.66 [CC(O)N], 162.97 [C(O)CCH2]. Found (%): C, 53.42; H, 5.27; N,
12.01; P, 5.30. Calc. for C26H30O9N5P (%): C, 53.15; H, 5.11; N, 11.92;
P, 5.28.
N
NO2
Alk = Pri, Ar = 2-EtC6H4
F
C
Alk3P
Alk = Pri, Ar = Ph
Alk = Bu, Ar = Ph
O2N
O
Ar
N
O
EtO
2
– FCH2Me
A
B
O2N
N
1-Phenyl-3-(2,4,6-trinitro)phenyl-5-tributylphosphoniomethyl barbiturate
3b: mp 244 °C. IR (KBr, n/cm–1): 1342, 1538 (NO2), 1642, 1690 (C=O).
1H NMR (400 MHz, DMSO-d6) d: 0.91 (t, 9H, Me, JHH 7.0 Hz), 1.39
(m, 6H, MeCH2), 1.51 (m, 6H, MeCH2CH2), 2.09 (m, 6H, CH2CH2P),
3.15 (d, 2H, CH2P, JHP 11.0 Hz), 7.05 (d, 2H, o-H, JHH 7.1 Hz), 7.36 (t,
1H, p-H, JHH 7.0 Hz), 7.44 (t, 2H, m-H, JHH 7.0 Hz), 9.08 (s, 2H, m-H).
13C NMR (100.68 MHz, DMSO-d6) d: 13.75 (C21), 17.30 (d, C17,
O2N
N
NO2
PAlk3 O
Pr3i P
NO2
NO2
O2N
O
N
O
O
O
N
O
Et
2
1JCP 33 Hz), 18.50 (d, C18, 1JCP 30 Hz), 23.28 (d, C19, JCP 3 Hz), 23.97
3
(d, C20, JCP 10 Hz), 74.33 (C2), 124.30 (C15), 128.08 (C8), 129.11 (C6),
3a Alk = Pri
3b Alk = Bu
4
129.50 (C7), 130.19 (C5), 150.46 (C4), 159.64 (C1), 162.84 (C3). Found (%):
C, 55.02; H, 5.93; N, 10.90; P, 4.85. Calc. for C29H36O9N5P (%): C, 55.30;
H, 5.72; N, 11.13; P, 4.93.
Scheme 1
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© 2010 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2010, 20, 277–278
tional steric hindrances for an attack at the carbon atom of the
cyano group in zwitterion 1.
C(8)
C(7)
C(6)
Note that a similar reaction8 (pathway B in Scheme 1) using
a zwitterion like 1 but possessing an ortho-ethylphenyl substi-
tuent at the carbamate nitrogen leads to formation of oxazindione
4, probably, due to steric and electron effects provided by the
ortho-ethyl group.
C(25)
C(22)
C(9)
C(10)
O(1)
C(24)
C(28)
C(27)
C(5)
C(23)
C(26)
C(1)
N(1)
C(2)
N(2)
C(29)
C(17)
The molecular structure of 3b was unambiguously estab-
lished by single-crystal X-ray diffraction analysis (Figure 1).‡
Compound 3b is a zwitterion with the positively charged phos-
phonium CH2P+Bu3 fragment and a negative charge localized
over the chain of conjugated bonds O(1)–C(1)–C(4)–C(3)–O(3).
The sum of angles at the carbanion centre C(4) is 360°; this
fact in combination with the shortened bonds at the carbanion
centre C(1)–C(4) [1.410(3) Å] and C(3)–C(4) [1.389(3) Å]
and the elongated bonds C(1)–O(1) [1.236(2) Å] and C(3)–O(3)
[1.245(2) Å] confirm that a delocalization of the anion charge
takes place in O(1)–C(1)–C(4)–C(3)–O(3).
P(1)
O(2)
N(3)
C(4)
C(3)
O(4)
C(11)
C(18)
O(9)
O(3)
O(5)
C(19)
N(5)
C(12)
C(13)
C(16)
C(20)
C(21)
O(8)
C(15)
C(14)
N(4)
O(6)
O(7)
Figure 1 Molecular structure of 3b. Selected bond lengths (Å): C(1)–O(1)
1.236(2), C(1)–N(1) 1.435(3), C(1)–C(4) 1.410(3), N(1)–C(5) 1.449(3),
N(1)–C(2) 1.370(3), C(2)–O(2) 1.225(2), C(2)–N(2) 1.392(3), N(2)–C(11)
1.412(3), N(2)–C(3) 1.437(2), C(1)–O(1) 1.236(2), C(1)–N(1) 1.435(3),
C(1)–C(4) 1.410(3), N(1)–C(5) 1.449(3), N(1)–C(2) 1.370(3), C(2)–O(2)
1.225(2), C(2)–N(2) 1.392(3), N(2)–C(11) 1.412(3), N(2)–C(3) 1.437(2),
C(3)–O(3) 1.245(2), C(3)–C(4) 1.389(3), C(4)–C(17) 1.504(3), C(1)–C(4)
1.410(3), C(11)–C(12) 1.398(3), C(12)–C(13) 1.381(3), C(13)–C(14)
1.380(3), C(14)–C(15) 1.374(3), C(15)–C(16) 1.384(3), C(16)–C(11)
1.395(3), C(12)–N(3) 1.487(3), C(14)–N(4) 1.470(3), C(16)–N(5) 1.482(3);
selected bond angles (°): C(3)–C(4)–C(1) 123.8(2), C(3)–C(4)–C(17)
119.3(2), C(1)–C(4)–C(17) 117.4(2).
This study was supported by the Russian Foundation for
Basic Research (project no. 08-03-00196).
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Crystallographic data for 3b: C29H36N5O9P, M = 629.60), monoclinic,
space group P21/c, at 120 K: a = 14.548(1), b = 9.0819(8) and c =
= 22.855(2) Å, b = 93.108(2)°, V = 3015.4(4) Å3, Z = 4, dcalc = 1.387 g cm–3,
crystal dimensions 0.45×0.30×0.20 mm, m(MoKα) = 1.53 cm–1, 2q < 58°.
32162 reflections were measured, 8018 unique reflections (Rint = 0.0702),
4053 reflections with I > 2s(I). The refinement converged to R1 =
= 0.0500, wR2 = 0.1002 with 400 refined parameters in a weighting
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,
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for CH or Me groups, respectively. All calculations were performed
using the SHELXTL software.10
8
9
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CCDC 756574 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2010.
Received: 29th March 2010; Com. 10/3497
– 278 –