C-phosphorylated pyrrolylcarbaldehydes

Article abstract of DOI:10.1002/hc.10137

The application of N,N-dimethylhydrazone protective group for synthesis of C-phosphorylated aldehydes of the pyrrole series was studied. The phosphorylation of the hydrazone with two equivalents of phosphorous tribromide in pyridine took occurred at posit

Full text of DOI:10.1002/hc.10137

Heteroatom Chemistry
Volume 14, Number 3, 2003
C-Phosphorylated Pyrrolylcarbaldehydes
Sergey P. Ivonin,1 Andrew A. Tolmachev,2 Tatyana E. Terikovska,2
Andrew A. Anishchenko,1 Alexandra A. Chaikovskaya,2 and
Alexander M. Pinchuk2
1Dnepropetrovsk State University, Dnepropetrovsk-10, 49625, Ukraine
2Institute of Organic Chemistry of the Ukrainian Academy of Sciences, 02094, Kiev-94, Ukraine
Received 21 February 2002; revised 22 October 2002
reaction with 2-pyrrolylaldehyde hydrazone (1) pro-
ABSTRACT: Application of N,N-dimethylhydrazone
ceeds not regioselectively but leads to a mixture
protective group for synthesis of C-phosphorylated
of products. In the 31P NMR spectra of these mix-
aldehydes of the pyrrole series was studied. Re-
tures two most intensive signals at δ = 106.8 and
moval of the hydrazone protection in monophos-
137.7 ppm in 1:6 ratio were observed, indicating that
phorylated pyrrolylcarbaldehyde hydrazones occurs
phosphorylation at ꢀ and ꢁ positions respectively
smoothly, while in biphosphorylated derivatives it re-
took place. No individual compound could be iso-
ꢀ
C
sults in nitrile formation.
2003 Wiley Periodicals,
lated from the reaction mixture.
Inc. Heteroatom Chem 14:258–261, 2003; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.10137
Phosphorylation of the hydrazone 1 with two
equivalents of phosphorus tribromide in pyridine
takes place at positions 2 and 5 of the heterocy-
cle with the formation of bisdibromophosphine (2),
which can be easily converted into corresponding
bisthioamide 3.
INTRODUCTION
Previously we have shown that the application
of N,N-dimethylhydrazone protective group makes
possible the synthesis of C-phosphorylated deriva-
tives of furfurol and 2-thienylcarbaldehyde [1,2]. In
the phosphorylation the hydrazone group acts not
only as an orienting but also as a strongly activat-
ing group. This allowed the synthesis not only of
mono- but also of biphosphorylated furfurol deriva-
tives. In the present work we used the method we
have developed to obtain the previously unknown C-
phosphorylated pyrrolylcarbaldehydes.
RESULTS AND DISCUSSION
Unlike the reaction of phosphorus tribromide with
furfurol and 2-thiophene aldehyde hydrazones, the
1
In the H NMR spectrum of 3 a triplet at δ =
6.5 ppm for the proton in the position 4 of the pyrrole
ring and a singlet for the CH N proton at 8.05 ppm
can be observed.
Correspondence to: S. P. Ivonin; e-mail: ivonin@dp.ukrtel.net.
c
ꢀ
2003 Wiley Periodicals, Inc.
258

C-Phosphorylated Pyrrolylcarbaldehydes 259
Selective monophosphorylation of
1
was
10 and presence of a signal because of exocyclic pro-
ton of hydrazone group at 8.08 ppm indicate that the
phosphorylation took place at the ring.
achieved with diphenylbromophosphine in pyridine
at room temperature. The resulting phosphine 4
(δ 31P = −18.0 ppm) was converted into the phos-
phine oxide 5 by hydrogen peroxide in good yield.
There are several methods of conversion of a hy-
drazone into an aldehyde group described in the lit-
erature [3]. These methods are mostly based on oxi-
dation or hydrolysis of the hydrazone group in strong
acid media. We have chosen the method that in-
cludes preliminary activation of the C N bond of the
hydrazone by alkylation of the amine nitrogen atom.
The subsequent acidic hydrolysis can be then car-
ried out under mild conditions. This method makes
it possible to regenerate the carbonyl group despite
the well-known low stability of the heterocycles in
question in acid media. By alkylation with methyl
iodide and subsequent hydrolysis, phosphine oxide
5 and thioamide 10 were converted into the aldehy-
des 11 and 12 respectively.
Presence of two doublets of doublets at δ = 6.28
and 5.05 ppm for 4-H and 3-H and a singlet for CH N
at 7.26 ppm in the 1H NMR of 5 indicate that the re-
action had occurred at position 5 of the heterocycle.
Phosphine oxide 5 can be regioselectively phos-
phorylated with phosphorus tribromide at posi-
tion 3. Dibromophosphine 6 thus obtained (δ 31P =
143 ppm, 15 ppm) was not isolated because of its low
stability and was converted into the thioamide 7 in
high yield.
The removal of the hydrazone protection in 3 and
7 was made similarly but in this case the nitriles 13
and 14 were obtained.
The phosphorylation of hydrazone 8 with phos-
phorus tribromide yields the dibromophosphine
9 (δ 31P = 141 ppm) which was converted into
thioamide 10.
The structures of 13 and 14 are supported by
the absence in the IR spectra of a characteristic ab-
sorption band corresponding to the aldehyde group
and presence of an absorption band at 2240 cm−1
which can be assigned to the nitrile group. In the
1H NMR spectrum of nitriles 13 and 14, no signals
due to proton of the aldehyde group can be observed
either.
The formation of nitriles in this reaction is
probably caused by the increased acidity of hy-
drogen atom of hydrazonium group owing to the
effect of two electron-withdrawing phosphorous
substituents.
The absence of signals for protons of the hetero-
cyclic system in the 1H NMR spectrum of compound

260 Ivonin et al.
The carbonyl group in aldehydes 11 and 12
hydrogen peroxide was added slowly with stirring
in such a way that the temperature of the reaction
mixture did not exceed 5◦C. Subsequently, the reac-
tion mixture was kept for 2 h at room temperature,
the organic layer was separated, neutralized with 5%
solution of NaOH, washed with water (3 × 50 ml),
dried with sodium sulphate, and the solvent was re-
moved in vacuo. The residue was treated with diethyl
ether. Yield 60%, m.p. 136–138◦C. 1H NMR (CDCl3),
δ: 2.07s (6H, N CH3); 3.27s (3H, N CH3); 5.05dd
(1H, H3, JPH = 0.9 Hz, JHH = 4.2 Hz); 6.26dd, (1H, H4,
JPH = 1.2 Hz, JHH = 4.2 Hz); 7.26s (1H, CH N); 7.50–
7.80m (10H, Ph). 31P NMR (CDCl3), δ: 18.2. Found:
N, 12.01; P, 8.92. C20H22N3OP (calculated): N, 11.97;
P, 8.83.
demonstrates characteristic behavior, e.g. reaction
with phenylhydrazine to the corresponding phenyl-
hydrazones 15 and 16.
3-Dimorpholinothiophosphoryl-5-
diphenylphosphoryl-1-methyl-1H-pyrrole-2-
carbaldehyde N,N-Dimethylhydrazone (7)
EXPERIMENTAL
1H and 31P NMR spectra were recorded on Varian
VXR 300 using TMS as internal standard for 1H NMR
and 85% H3PO4 as external standard for 31P NMR
spectra. All experiments were carried out in water-
free solvents.
To a solution of 1 mmol of 5 in 20 ml of pyridine
a solution of 1 mmol of phosphorus tribromide in
5 ml of pyridine was added. The reaction mixture
was kept for 72 h at room temperature. A solution
of 2 mmol of morpholine and 3 mmol of triethy-
lamine in 10 ml of benzene was added. In 30 min
the 1 mmol of sulphur was added and the result-
ing mixture was heated over 2 h at 70◦C. The pre-
cipitate was filtered off, the solvent was evaporated
in vacuo, and the residue was treated with diethyl
ether. Yield 45%, m.p. 210–211◦C. 1H NMR (CDCl3),
δ: 2.60–3.20m (14H, N(CH3)2 + N CH2); 3.30–3.50m
(8H, O CH2); 3.84s (3H, N CH3); 6.63t (1H, Het,
JPH = 1.0 Hz), 6.90–7.70m (10H, Ph); 7.99s (CH N).
31P NMR (CDCl3), δ: 18.9, 66.8. Found: N, 12.34; P,
10.76. C28H37N5O3P2S (calculated): N, 12.57; P, 10.92.
3,5-Bis(dimorpholinothiophosphonate)-1-
methyl-1H-pyrrole-2-carbaldehyde
N,N-Dimethylhydrazone (3)
To a solution of 1 mmol of 1 in 50 ml of pyridine a
solution of 2 mmol of phosphorus tribromide in 5 ml
of pyridine was added at 5◦C with stirring. In 48 h,
to the reaction mixture a solution of 4 mmol of mor-
pholine and 6 mmol of triethylamine in 150 ml of
benzene was added. In 30 min the precipitate was
filtered off, to the filtrate 2 mmol of sulphur was
added and the resulting mixture was heated over 2 h
at 80◦C. The solvent was evaporated in vacuo and the
product was obtained by crystallization from octane.
Yield 54%, m.p. 181–183◦C. 1H NMR (CDCl3), δ: 3.02s
(6H, N (CH3)2); 3.05–3.30m (16H, N CH2); 3.50–
3.80m (16H, O CH2); 4.13s (N CH3); 6.51t (1H, Het,
JPH = 1.2 Hz), 8.05s (CH N). 31P NMR (CDCl3), δ:
60.5, 67.8. Found: N, 16.01; P, 10.14. C28H37N5O3P2S
(calculated): N, 15.83; P, 10.02.
4-Dimorpholinothiophosphoryl-1-(p-tolyl)-2,5-
dimethyl-1H-pyrrole-2-carbaldehyde
N,N-Dimethylhydrazone (10)
To a solution of 1 mmol of 8 and 1 mmol of triethy-
lamine in 20 ml of benzene a solution of 1 mmol
of phosphorus tribromide in 5 ml of benzene was
added. The reaction mixture was kept for 2 h at room
temperature and a solution of 2 mmol of morpho-
line and 2 mmol of triethylamine in 10 ml of ben-
zene was added. In 30 min to the reaction mixture
1 mmol of sulphur was added and the mixture was
heated at 70◦C for 2 h. The precipitate was filtered
off and the solvent from the filtrate was removed in
vacuo. The product was obtained by crystallization
5-(Diphenylphosphoryl)-1-methyl-1H-pyrrole-2-
carbaldehyde N,N-Dimethylhydrazone (5)
To a solution of 2 mmol of 1 in 10 ml of pyridine
a solution of 2 mmol of diphenylbromophosphine
in 10 ml of pyridine was added. The reaction mix-
ture was kept for 24 h at room temperature, the
precipitate was filtered off, and the solvent was re-
moved from the filtrate in vacuo. The residue was
dissolved in 100 ml of chloroform, and 15 ml of 30%
from ethanol. Yield 60%, m.p. 181–183◦C. H NMR
(CDCl3), δ: 2.13s (3H, C CH3); 2.28s (3H, C CH3);
2.44s (3H, C CH3); 2.90s (6H, N CH3); 3.18m (8H,
1

C-Phosphorylated Pyrrolylcarbaldehydes 261
cm−1 band corresponding to C N bond. Found: N,
10.24; P, 11.51. C26H30N4O3P2S (calculated): N, 10.37;
P, 11.48.
N CH2); 3.67m (8H, O CH2); 7.02d (2H, o-H, JHH
=
8.4 Hz); 7.29d (2H, m-H, JHH = 8.4 Hz); 8.08s (1H;
CH N). 31P NMR (CDCl3), δ: 67.5. Found: N, 14.21;
P, 6.32. C24H36N5O2PS (calculated): N, 14.30; P, 6.33.
2-Cyano-1-methyl-1H-pyrrole-3,5-
bis(dimorpholinothiophosphonate) (14)
5-(Diphenylphosphoryl)-1-methyl-1H-pyrrole-2-
carbaldehyde (11)
The product is obtained from 3 using the method
similar to the one described above for nitrile 13.
Yield 33%, m.p. 225–226◦C. 1H NMR (CDCl3), δ: 2.65–
3.07m (16H, N CH2); 3.42–3.76m (16H, O CH2);
3.76s (3H, N CH3); 6.18 br s (1H, Het). 31P NMR
(CDCl3), δ: 18.7, 66.3. IR: 2240 cm−1 band corre-
sponding to C N bond. Found: N, 16.27; P, 12.15.
C22H36N6O4P2S2 (calculated): N, 16.41; P, 12.11.
To 5 mmol of 5, 5 ml of ethyliodide was added, the
mixture was boiled for 4 h, and then the solvent was
removed in vacuo. The residue was dissolved in 50 ml
of 3% hydrochloric acid solution and was heated
for 10 h at 80–85◦C. The reaction mixture under-
went extraction with chloroform several times; af-
terwards chloroform was removed in vacuo and the
product was obtained by crystallization from hep-
1
tane. Yield 30%, m.p. 64–65◦C. H NMR (CDCl3), δ:
5-Diphenylphosphoryl-1-methyl-1H-pyrrole-2-
carbaldehyde Phenylhydrazone (15)
4.00s (3H, N CH3); 6.07dd (1H, H3, JPH = 1.0 Hz,
JHH = 1.5 Hz); 7.03dd (1H, H4, JPH = 1.3 Hz, JHH
=
1.5 Hz); 7.50–8.10m (10H, Ph); 9.75s (1H, CH O).
31P NMR (CDCl3), δ: 18.4. Found: N, 4.31; P, 9.96.
C18H16NO2P (calculated): N, 4.53; P, 10.03.
To a solution of 1 mmol of 11 in 5 ml of ethanol a
solution of 1 mmol of phenylhydrazine in 5 ml of
ethanol and catalytic amount of p-toluenesulphonic
acid were added. The mixture was heated for 2 h at
50◦C, and the precipitate thus formed was filtered
off. Yield 88%, m.p. 132–133◦C. 1H NMR (CDCl3), δ:
3.97s (3H; N CH3); 5.97t J = 3.0 Hz (1H; H3); 6.28t
J = 3.0 Hz (1H; H4); 6.84t J = 9.0 Hz (1H, p-Ph);
6.98d J = 9.0 Hz (1H, o-Ph); 7.23t J = 9.0 Hz (1H, m-
Ph); 7.50–7.75m (10H, Ph) 7.95s (1H; CH N). Found:
N, 10.24; P, 7.32. C24H22N3OP (calculated): N, 10.53;
P, 7.77.
4-Dimorpholinothiophosphoryl-1-(p-tolyl)-2,5-
dimethyl-1H-pyrrole-2-carbaldehyde (12)
A solution of 10 mmol of 10 in 20 ml of methyl
iodide was boiled for 5 h. The precipitate was fil-
tered off and dissolved in 10 ml of 1% solution of hy-
drochloric acid. The reaction mixture was boiled for
3 h. The product was extracted with methylene chlo-
ride (2 × 20 ml). The organic layer was separated,
dried with sodium sulphate, and the solvent was re-
moved in vacuo. The product was obtained by crys-
tallization from ethanol. Yield 40%, m.p. 214–215◦C.
1H NMR (CDCl3), δ: 2.29s (3H, C CH3); 2.32s (3H,
C CH3); 2.45s (3H, C CH3); 3.17m (8H, N CH2);
3.69m (8H, O CH2); 7.00d (2H, o-H, JHH = 8.7 Hz);
7.34d (2H, m-H, JHH = 8.7 Hz); 10.65s (1H; CH O).
NMR 31P (CDCl3), δ: 66.2. Found: N, 9.41; P, 6.83.
C22H30N3O3PS (calculated): N, 9.39; P, 6.92.
4-Dimorpholinothiophosphoryl-1-(p-tolyl)-2,5-
dimethyl-1H-pyrrole-2-carbaldehyde
Phenylhydrazone (16)
A solution of 10 mmol of 12 and 10 mmol of phenyl-
hydrazine in 20 ml of ethanol was boiled for 2 h.
The solvent from the reaction mixture was evap-
orated in vacuo and the product was obtained by
crystallization from octane. Yield 90%, m.p. 159–
160◦C. 1H NMR (CDCl3), δ: 2.08s (3H, C CH3); 2.27s
(3H, C CH3); 2.46s (3H, C CH3); 2.90s 3.19m, (8H,
N CH2); 3.68m (8H, O CH2); 7.0–7.4m (9H, Ar +
Ph); 8.57s (1H; CH N). Found: N, 12.95; P, 5.82.
C28H36N5O2PS (calculated): N, 13.03; P, 5.76.
2-Cyano-1-methyl-1H-pyrrole-5-diphenylphos-
phoryl-3-dimorpholinothiophosphonate (13)
To 1 mmol of 8, 5 ml of ethyl iodide was added. The
mixture was boiled for 7 h and the solvent was re-
moved in vacuo. To the residue thus formed 50 ml
of 3% solution of hydrochloric acid was added and
the reaction mixture was heated for 96 h at 85◦C.
The formed precipitate was recrystallized from oc-
tane. Yield 37%, m.p 233–234◦C. 1H NMR (CDCl3), δ:
2.70–3.10m (8H, N CH2); 3.40–3.70m (8H, O CH2);
3.80s (3H, N CH3); 6.24 br s (1H, Het); 7.50–7.85m
(10H, Ph). NMR 31P (CDCl3), δ: 60.5, 67.3. IR: 2240
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[2] Tolmachev, A. A.; Ivonin, S. P.; Anishchenko, A. A.;
Pinchuk, A. M. Heteroatom Chem 1998, 9, 461–470.
[3] McOmie, J. F. W. (Ed.). Protective Groups in Organic
Chemistry; Plenum Press: London, 1973; p. 391.