Phosphorylation of derivatives of β-dialkyaminocrotonitriles with phosphorus(III) halides

Article abstract of DOI:10.1002/hc.20532

The reaction of β-dialkylaminocrotontriles with phosphorus(III) halides has been investigated. The basicity of the dialkylamino group influences the phosphorylation markedly, with pyrrolidine being the amine of choice. It was found that a solvent and the

Full text of DOI:10.1002/hc.20532

Heteroatom Chemistry
Volume 20, Number 4, 2009
Phosphorylation of Derivatives of
β-Dialkyaminocrotonitriles with
Phosphorus(III) Halides
Aleksandr N. Kostyuk, Yurii V. Svyaschenko,
Bogdan B. Barnych, Dmitriy A. Sibgatulin, Eduard B. Rusanov,
and Dmitriy M. Volochnyuk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
Murmanska 5, Kyiv 94, 02094, Ukraine
compounds embedding the double C C bond bear-
ABSTRACT: The reaction of β-dialkylaminocroton-
ing electron-releasing substituents, for example,
triles with phosphorus(III) halides has been in-
alkylvinylether [2] and N,N-dialkylhydrazones
vestigated. The basicity of the dialkylamino group
[3]. In our previous works, we have shown that
influences the phosphorylation markedly, with pyrro-
enamines can also be subjected to the reactions with
lidine being the amine of choice. It was found
phosphorus halides and the deactivated enamines
that a solvent and the ratio of triethylamine play a
were demonstrated to be readily phosphorylated
significant role in phosphorylation. Although chloro-
with phosphorus(III) halides affording stable
and dichlorophosphine derivatives proved impos-
derivatives [4]. Contrary to that the linear enamines
sible to separate as individual compounds; their
such as 2-morpholinoprop-1-ene are easily phos-
solutions can be successfully used for further
phorylated with phosphorus trichloride, affording
ꢀ
C
transformations.
2009 Wiley Periodicals, Inc. Het-
dichlorophosphine derivatives that upon further
treatment with triethylamine undergo C P bond
cleavage [5]. In addition, 2-methylpropenylidenebis-
dimethylamine behaves in the reaction with
phosphorus trichloride analogously [6]. An analysis
of the literature data showed that deactivated
enamines are the most suitable substrates for these
reactions. Two tendencies should be taken into
account. Introducing electron-withdrawing groups
into the conjugation chain or obstructing the conju-
gation between a dialkylamino group and a double
bond makes these enamines less nucleophilic, so
that a smaller set of phosphorus electrophiles would
react with them. The advantage of the decreased
activity of the enamine would be stronger C P bond
at halogen and dihalogenphosphine derivatives
so that in the reactions with various nucleophiles
C P bond might remain intact. One of the ways
to decrease enamine reactivity is the introduction
eroatom Chem 20:194–201, 2009; Published online in
Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20532
INTRODUCTION
For over half a century, the interest in enamines
has not been abated. Many reviews and books
have appeared in this time. The most complete
review on enamines persuasively shows them as
C-nucleophiles that can be used in numerous
reactions with various electrophiles [1]. At the same
time, phosphorus halides, powerful electrophiles,
are widely used in organophosphorus chemistry
in electrophilic substitution reactions with many
Correspondence to: A.Kostyuk@enamine.net.
2009 Wiley Periodicals, Inc.
c
ꢀ
194

Phosphorylation of Derivatives of β-Dialkyaminocrotonitriles with Phosphorus(III) Halides 195
R
R
CN
This paper
R
CN
Ref. [8,9]
CN
OAlk
OAlk
+
Alk2N
Alk2N
P(V)
Alk2N
P(V)
R′2P-Hal
+
FIGURE 1
of an electron-withdrawing group at the β-position
of enamines. Owing to the extended conjugation
chain, these enamines are remarkably deactivated.
Thus, derivatives of 3-dialkylaminocrotonic acid
are the simplest stabilized push–pull enamines.
Previously, these enamines were shown to react
with diphenylchlorophosphine [7].
Phosphorylated derivatives of these enamines
could be prepared by the condensation of activated
methylene compounds with lactam acetals [8] or
electrophilic thioiminium intermediates [9] (see
Fig. 1).
As the starting enamines are widely used in
heterocyclic synthesis, one can expect that their
phosphorylated derivatives can also be used in
similar types of transformation, affording phospho-
rylated heterocycles or phosphaheterocycles as it
has been already demonstrated [10].
dichlorophosphine 2a. In this case, in 30 min in
the reaction mixture the ratio of major isomer of
dichlorophosphine to phosphorus trichloride was
1: 0.28, but in 6 days it changed to 1.78:1. Excess
of triethylamine, 1.3–2 equiv, helps to consume
the phosphorus trichloride completely, but on pro-
longed standing its traces reappear in the reaction
mixture. We have found that it would be best to use
1.3 equivalents of triethylamine so that in 22 h all
phosphorus trichloride is consumed and the isomers
of dichlorophosphine 2 in 1:0.17 ratio formed. In
almost every case, we registered a small admixture
of an unidentified phosphorus product with δP = −8.
It should be noted that almost an analogous pat-
tern of phosphorylation was observed in benzene.
In this case to convert all phosphorus trichloride,
1.3 equiv of triethylamine is also required. After
15–20 h, the reaction mixture contains two isomers
of dichlorophosphine 2a in 1:0.17 ratio as well
as small amount of an unidentified phosphorus
product with δP = −8.
RESULTS AND DISCUSSION
A decrease in the basicity of dialkylamine from
pyrrolidine to morpholine considerably deteriorated
the reaction, so that phosphorylation of enamine
1b proceeded nonregioselectively, affording many
by-products. In benzene, even the use of 1.5 equiv
of triethylamine is not sufficient to convert all
phosphorus trichloride.
Continuing our research on the phosphorylation of
enamines with phosphorus(III) halides, we inves-
tigated reactions of push–pull enamines, namely 1
both pyrrolidine and morpholine derivatives with
various phosphorus(III) halides.
We have started our research with the reaction
of phosphorus trichloride with these enamines in
the presence of triethylamine in various solvents
(Scheme 1).
The phosphorylation of enamine 1a with phos-
phorus trichloride was studied in dichloromethane
at room temperature with 1:1 molar ratio of the
reagents changing amount of triethylamine from
1 to 2 equiv. It should be noted that the amount
of triethylamine has a remarkable effect on the
reaction. One equivalent of triethylamine is not
sufficient to convert all phosphorus trichloride into
Our attempt to separate dichlorophosphines
2 as individual compounds failed. After removing
solvents, a set of unidentifiable products are present
in the residue. Thus, we recommend further use
of dichlorophosphine 2a without separation and
purification.
As pyrrolidine enamine 1a reacted much bet-
ter with phosphorus trichloride when compared
with morpholine derivatives 1b, the former was
selected for further investigations. A solution of
Me
CN
Me
CN
PCl3, Et3N
N
N
; b:
O
R2N = a:
.
R2N
2a,b
Et3N HCl
PCl2
R2N
1a,b
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

196 Kostyuk et al.
CN
Me
N
CN
Me
N
X
2HNR2
2Et3N
P(NR2)2
P(NR2)2
X
4a X=O
4b X=S
3
CN
Me
N
Me
N
CN
2a
Δ
P(NR2)2
N
P(NR2)2
N
NAr
ArN
5a–c
6a–c
Me
CN
N
O
NR2=
N
P(OEt)2
1. 2 EtOH, 2Et3N
2.S
S
7
Cl
Ar = 5a, 6a: Ph; 5b, 6b: C6H4NO2 o; 5c, 6c:
O
SCHEME 2
dichlorophosphine 2a prepared by an optimized
procedure in dichloromethane was used for fur-
ther transformations with secondary amines and
alcohols.
phosphorus trichloride in molar ratios 2:1 and
3:1 changing amount of triethylamine. Unfortu-
nately in all cases, we failed to separate individual
chlorophosphines or their derivatives. When phos-
phorylation was run in dichloromethane in the mo-
lar ratio enamine:phosphorus trichloride 2:1 with 2
equiv of triethylamine judging from 31P NMR, it led
to the formation of four products with δp = 168.1,
163.3, 94.4, and −7.4 in the ratio 1:0.18:0.19:0.06.
Signals δp = 168.1, 163.3 can be attributed to isomers
of dichlorophosphine 2a; signal δp = 94.4 may ten-
tatively be assigned to the targeted chlorophosphine
bearing two enamine residues. Unfortunately with
time, the reaction mixture slowly decomposes lead-
ing to the appearance of phosphorus trichloride and
decreasing intensities of other signals. The increase
in the molar ratio of triethylamine from 2.5 to 3 equiv
does not change the situation markedly. We also
failed to introduce three enamine residues. With the
molar ratio enamine:phosphorus trichloride 3:1 with
3 equiv of triethylamine, the reaction mixture con-
tains low-intensity signals, which slowly degrade.
From phosphorus trichloride to dichlorophos-
Compound 3 was prepared by the reaction of
dichlorophosphine 2a with 2 equiv of morpholine
in the presence of 2 equiv of triethylamine. The
behavior of phosphonite 3 in oxidation reactions
is quite typical for this class of compounds. Thus,
it was easily oxidized with hydrogen peroxide and
sulfur into phosphonates 4a and 4b, respectively
(see Scheme 2). It also reacted readily with a set
of arylazides, affording phosphazides 5a–c that
were converted into the corresponding iminophos-
phonates 6a–c. The constitution of compounds
5c and 6c was confirmed by the X-ray analysis.
It should be noted that both the compounds are
E-isomers, where pyrrolidine and nitrile groups
are placed on the same side of the double bond.
CCDC-675031 for 5c and CCDC-675032 for 6c
contain all 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.
phines,
a pattern of phosphorylation remains
Thiophosphonate 7 was prepared without sepa-
rating a trivalent phosphonite.
With the aim of substituting two and eventually
three enamine residues at phosphorus, we have
studied the phosphorylation of enamine 1a with
analogous. The phosphorylation of enamine 1a was
studied in dichloromethane varying the amount
of triethylamine from 1 to 2 equiv. In all cases, in
30 min all phenyldichlorophosphine was consumed,
affording two isomers of chlorophosphine 10 in the
Heteroatom Chemistry DOI 10.1002/hc

Phosphorylation of Derivatives of β-Dialkyaminocrotonitriles with Phosphorus(III) Halides 197
CN
Me
Me
N
MePCl2
Et3N
Me
N
CN
P
1. O(CH2CH2)2NH
2. S
1a
P
N
Me
O
X
Cl
8
9a,b
1. p-NO2C6H4N3
2. O(CH2CH2)2NH
PhPCl2, Et3N
X = 9a: S; 9b: NC6H4NO2
p
CN
Me
CN
P
Me
N
1. O(CH2CH2)2NH
2. [O]
P
N
O
N
Cl
Ph
O
Ph
10
11
SCHEME 3
ratio 1:0.16 (δp = 94.1 and 87.5). When 1 equiv of tri-
ethylamine is used in 8 h phenyldichlorophosphine
reappears in the reaction mixture. When more than
1.3 equiv of triethylamine is used, an admixtures
with signals −14.1 and −20.7 appear in the reaction
mixture, and their intensities grow on standing.
Thus the optimum amount of triethylamine is 1.1
equiv. In this case, the reaction runs cleanly, afford-
ing two isomers of chlorophosphine 10 in the ratio
1:0.16. Chlorophosphine 10 is a typical of its class,
and as an example it was transformed into phosphi-
nate 11 by reacting with morpholine followed by the
oxidation with hydrogen peroxide (see Scheme 3).
Both in dichloromethane and benzene, the phos-
phorylation of enamine 1a with methyldichloro-
phosphine also runs cleanly, but requires slight
excess of triethylamine: 1.2–1.3 equiv. Chlorophos-
phine 8 readily reacts with morpholine and then with
sulfur, affording thiophosphinate 9a. It is also suf-
ficiently nucleophilic to react with arylazides. Thus
iminophosphinate 9b was prepared by the oxidation
EXPERIMENTAL
General
All procedures with compounds sensitive to hydroly-
sis and oxidation were carried out in an atmosphere
of dry argon. All solvents were purified and dried by
standard methods. NMR spectra were recorded on
a Varian VXR-300 spectrometer: H and 13C NMR
1
(300 and 75.4 MHz, respectively), C6D6 and CDCl3
as solvents with TMS as an internal standard; 31P
(121 MHz) with 85% H3PO4 as an external standard,
in CHCl3. IR spectra were recorded on a Nexus-470
spectrometer for samples in KBr disks. Mass spectra
were obtained on VG 70–70EQ, VG Analytical (FAB)
for substances 5a–c or a MX-1321 instrument (EI,
70 eV) by a direct inlet for other substances. Mi-
croanalyses were performed in the Microanalytical
Laboratory of the Institute of Organic Chemistry,
National Academy of Sciences of Ukraine. Melting
points are uncorrected. Yields refer to pure isolated
products. The starting enamines were prepared
according to the literature [11].
of chlorophosphine
8 with p-nitrophenylazide
followed by the reaction with morpholine.
2-Dichlorophosphanyl-3-pyrrolidin-1-yl-but-2-
enenitrile 2a
CONCLUSION
Solution in Dichloromethane. To a solution
of phosphorus trichloride (1.01 g, 7.3 mmol) in
dichloromethane (10 mL), a mixture of enamine 1a
(1 g, 7.3 mmol) and triethylamine (0.96 g, 9.5 mmol)
in dichloromethane (10 mL) was added dropwise
at temperature −20◦C. The reaction mixture was
allowed to warm to room temperature. After 20–
22 h judging by 31P NMR, the reaction mixture con-
tains two isomers of dichlorophosphine 2a, δp = 168
and 163 in the ratio 1:0.17. The reaction mixture
Although the phosphorylation of β-dialkyaminocro-
tonitriles with phosphorus(III) halides requires fine-
tuning of the reaction conditions, it can be used for
synthesizing various phosphorus derivatives. It was
shown that one enamine residue can be introduced
at phosphorus halides that can be further trans-
formed into stable three- and pentavalent deriva-
tives. The basicity of the dialkylamine in the enam-
ines and the amount of a base play a significant role.
Heteroatom Chemistry DOI 10.1002/hc

198 Kostyuk et al.
contains an unidentified product with δp = −8 ca.
4%–5%.
2-(Dimorpholin-4-yl-phosphorothioyl)-3-
pyrrolidin-1-yl-but-2-enenitrile 4b
In benzene, the reaction was run analogously at
10◦C. After 20 h, the reaction mixture can be used
for further transformations.
To a stirred solution of PCl3 (1.01 g, 7.3 mmol)
in benzene (20 mL) under dry argon, a solution
of enamine 1a (1 g, 7.3 mmol) and Et3N (0.96 g,
9.5 mmol) in benzene (20 mL) was added dropwise.
After 20 h, to the stirred solution obtained, a solu-
tion of morpholine (1.28 g, 14.6 mmol) and Et3N
(1.48 g, 14.6 mmol) in benzene (20 mL) was added
dropwise. After 1 h, finely ground sulfur (0.119 g,
3.7 mmol) was added. The reaction mixture was
stirred until complete dissolution of the sulfur in
4 h. The reaction mixture was washed with water.
The organic phase was separated, dried (Na2SO4),
and evaporated in vacuo. The residue was crystal-
lized from i-PrOH. Brown solid (1.48 g, 56%). Mp
140–142◦C. 31P NMR: δ = 74.9. 1H NMR (CDCl3):
δ = 1.98 (bs, 4H, CH2), 2.48 (s, 3H, CH3), 3.2 (m,
8H, PNCH2), 3.71 (m, 12H, OCH2 (8H), NCH2).
13C NMR (CDCl3): δ = 22.3 (C(4)), 24.8 (CH2), 25.7
(CH2), 45.5 (PNCH2), 51.2 (NCH2), 53.0 (NCH2), 66.1
(1 JCP = 154 Hz, C(2)), 66.9 (3 JCP = 7.5 Hz, OCH2),
121.1 (2 JCP = 8.8 Hz, CN), 169.1 (2 JCP = 20.1 Hz,
C(3)). MS, m/z (%): 370 (M+, 29), 285 (53), 252 (99),
199 (45), 197 (47), 165 (57), 136 (93), 86 (100), 70
(34), 56 (33), 43 (36). Anal. Calcd for C16H27N4O2
PS: C 51.88, H 7.35, N 15.12, P 8.36, S 8.66. Found:
C 51.57, H 7.14, N 14.95, P 8.01, S 8.16.
2-(Dimorpholin-4-yl-phosphino)-3-pyrrolidin-1-
yl-but-2-enenitrile 3
To a stirred solution of PCl3 (1.01 g, 7.3 mmol)
in benzene (20 mL) under dry argon, a solution
of enamine 1a (1 g, 7.3 mmol) and Et3N (0.96 g,
9.5 mmol) in benzene (20 mL) was added drop-
wise. After 20 h, a solution of morpholine (1.28 g,
14.6 mmol) and Et3N (1.48 g, 14.6 mmol) in benzene
(20 mL) was added dropwise. After 1 h, the reaction
mixture was washed with water. The organic phase
was separated, dried (Na2SO4), and evaporated in
vacuo. The residue is brown oil (1.4 g, 57%). 31P
1
NMR: δ = 97.7. H NMR (CDCl3): δ = 1.82–1.92 (m,
4H, CH2), 2.14 (s, 3H, CH3), 2.91–3.06 (m, 8H,
PNCH2), 3.52–3.67 (m, 12H, OCH2(8H), NCH2). 13C
NMR (CDCl3): δ = 19.8 (3 JCP = 40 Hz, C(4)), 25.3
(CH2), 48.1 (2 JCP = 13.8 Hz, PNCH2), 50.9 (NCH2),
67.9 (3 JCP = 7.5 Hz, OCH2), 70.3 (1 JCP = 18.9 Hz,
C(2)), 123.0 (CN), 163.8 (2 JCP = 36.5 Hz, C(3)). MS,
m/z (%): 338 (M+,11), 252 (100), 203 (76), 165 (91),
136 (28), 118 (80), 88 (25), 68 (55), 42 (31). Anal.
Calcd for C16H27N4O2P: C 56.79, H 8.04, N 16.56, P
9.15. Found: C 56.33, H 8.05, N 16.29, P 8.79.
General Procedures for Phosphotriazenes 5
To a stirred solution of PCl3 (1.01 g, 7.3 mmol)
in benzene (20 mL) under dry argon, a solution
of enamine 1a (1 g, 7.3 mmol) and Et3N (0.96 g,
9.5 mmol) in benzene (20 mL) was added drop-
wise. After 20 h, a solution of morpholine (1.28 g,
14.6 mmol) and Et3N (1.48 g, 14.6 mmol) in benzene
(20 mL) was added dropwise. After 1 h, the reaction
mixture was washed with water. The organic phase
was separated and dried (Na2SO4). An appropriate
arylazide was added, and the reaction mixture
was left to stand at room temperature overnight.
The precipitate formed was filtered, affording the
targeted compound 5.
2-(Dimorpholin-4-yl-phosphoryl)-3-pyrrolidin-1-
yl-but-2-enenitrile 4a
To a stirred solution of 3a (0.5 g, 1.5 mmol) in ben-
zene (30 mL), finely powdered H2O2·H2NC(O)NH2
was added. After 4 h, the reaction mixture was
washed with water. The organic phase was sepa-
rated, dried (Na2SO4), and evaporated in vacuo. The
residue is light brown oil (0.32 g, 61%). 31P NMR:
δ = 28.3. 1H NMR (CDCl3): δ = 1.93–2.02 (m, 4H,
CH2), 2.42 (s, 3H, CH3), 3.18–3.31 (m, 8H, PNCH2),
3
3.44–3.62 (bm, 2H, NCH2), 3.69 (t, JHH = 3.9, 8H,
OCH2), 3.75–3.94 (bm, 2H, NCH2). 13C NMR (CDCl3):
δ = 20.9 (C(4)), 24.8 (CH2), 25.7 (CH2), 44.9 (PNCH2),
51.1 (NCH2), 52.4 (NCH2), 60.4 (1 JCP = 143 Hz, C(2)),
67.2 (3 JCP = 5 Hz, OCH2), 121.3 (2 JCP = 11 Hz, CN),
168.8 (2 JCP = 16.3 Hz, C(3)). MS, m/z (%): 354 (M+,
8), 269 (30), 184 (45), 183 (100), 136 (79), 108 (13),
88 (25), 86 (24), 68 (22), 42 (17). Anal. Calcd for
C16H27N4O3P: C 54.23, H 7.68, N 15.81, P 8.74.
Found: C 54.10, H 7.71, N 15.52, P 8.39.
(2-[Dimorpholin-4-yl(3-phenyltriaz-2-enylidene)-
phosphoranyl]-3-pyrrolidin-1-yl-but-2-enenitrile 5a.
Yellow solid (2.17 g, 65%). Mp 182–186◦C. 31P NMR:
1
δ = 44.7. H NMR (CDCl3): δ = 1.94–2.05 (bm, 4H,
CH2), 2.36 (s, 3H), 3.32–3.41 (m, 8H, PNCH2), 3.45–
3.55 (bm, 2H, NCH2), 3.67–3.79 (bm, 8H, OCH2),
3
3.86–3.97 (bm, 2H, NCH2), 7.16 (t, JHH = 6.9 Hz,
Heteroatom Chemistry DOI 10.1002/hc

Phosphorylation of Derivatives of β-Dialkyaminocrotonitriles with Phosphorus(III) Halides 199
3
1H, 4-Ph), 7.32 (t, JHH = 6.9 Hz, 2H, 3-Ph), 7.45 (d,
3 JHH = 6.9 Hz, 2H, 2-Ph). 13C NMR (CDCl3): δ = 23.1
(C(4)), 24.6 (CH2), 25.6 (CH2), 45.3 (PNCH2), 51.4
(NCH2), 53.0 (NCH2), 56.5 (1 JCP = 173 Hz, C(2)), 66.8
(3 JCP = 5.2 Hz, OCH2), 120.5 (C(2ꢁ)), 125.5 (C(4ꢁ)),
128.6 (C(3ꢁ)), 151.6 (C(1ꢁ)), 169.6 (2 JCP = 16 Hz,
C(3)). MS FAB, m/z (%): 458 (M + 1, 78), 354 (53).
338 (32), 252 (100), 204 (17), 165 (27), 154 (46), 136
(33), 105 (21), 75 (26). Anal. Calcd for C22H32N7O2P:
C 57.76, H 7.05, N 21.43, P 6.77. Found: C 57.42, H
6.93, N 21.12, P 6.41.
General Procedure for Preparation of
Iminophosphonates 6
Phosphothriazene 5 (0.5 g) was heated in vacuo to
170◦C for 30 min, affording iminophosphonate 6.
(2-[Dimorpholin-4-yl(phenyl)phosphorimidoyl]-
3-pyrrolidin-1-yl-but-2-enenitrile 6a. Brown solid
(0.45 g, 95%). Mp 87–92◦C. 31P NMR: δ = 17.1. H
1
NMR (CDCl3): δ = 1.89–2.03 (bm, 4H, CH2), 2.26
(s, 3H), 3.21–3.34 (m, 8H, PNCH2), 3.46–3.94 (bm,
12H, OCH2 (8H), NCH2 (4H)), 6.68 (t, 3 JHH = 7.2 Hz,
3
1H, 4-Ph), 6.75 (d, JHH = 7.2 Hz, 2H, 2-Ph), 7.08
2-{Dimorpholin-4-yl[3-(2-nitrophenyl)triaz-2-en-
ylidene]phosphoranyl}-3-pyrrolidin-1-yl-but-2-eneni-
trile 5b. Yellow solid (1.65 g, 45%). Mp 160–164◦C.
3
(t, JHH = 7.2 Hz, 2H, 3-Ph). 13C NMR (DMSOd6):
δ = 20.4 (C(4)), 24.4 (CH2), 25.4 (CH2), 45.0 (PNCH2),
50.7 (NCH2), 52.4 (NCH2), 58.4 (1 JCP = 171 Hz, C(2)),
66.5 (3 JCP = 6 Hz, OCH2), 116.2 (C(4ꢁ)), 121.5
(2 JCP = 9.9 Hz, CN), 122.4 (3 JCP = 16.4 Hz, C(2ꢁ)),
128.5 (C(3ꢁ)), 150.9 (C(1ꢁ)), 168.8 (2 JCP = 15.6 Hz,
C(3)). MS, m/z (%): 429 (M+, 22), 259 (100), 252
(63), 183 (28), 167 (54), 122 (52), 93 (66), 86 (52), 70
(17), 56 (16), 42 (14). Anal. Calcd for C22H32N5O2P:
C 61.52, H 7.51, N 16.31, P 7.21. Found: C 61.55, H
7.43, N 16.19, P 6.92.
31P NMR: δ = 44.3. H NMR (CDCl3): δ = 1.95–2.11
1
(m, 4H, CH2), 2.28 (s, 3H), 3.22–3.41 (m, 8H,
3
PNCH2), 3.59 (t, JHH = 6.6 Hz, 2H, NCH2), 3.63–
3
3.75 (m, 8H, OCH2), 3.97 (t, JHH = 6.6 Hz, 2H,
3
NCH2), 7.15 (t, JHH = 6.6 Hz, 1H, 4-Ph), 7.43 (d,
3 JHH = 6.6 Hz, 1H, 6-Ph), 7.46–7.52 (m, 2H, Ph).
13C NMR (CDCl3): δ = 22.8 (C(4)), 24.7 (CH2), 25.7
(CH2), 45.2 (PNCH2), 51.7 (NCH2), 53.5 (NCH2),
56.0 (1 JCP = 166 Hz, C(2)), 66.8 (3 JCP = 5 Hz, OCH2),
120.6 (2 JCP = 8.8 Hz, CN), 123.7, 124.4, 125.2, 131.6,
143.2 (C(1ꢁ)), 145.2 (C(2ꢁ)), 170.2 (2 JCP = 18.9 Hz,
C(3)). MS FAB, m/z (%): 503 (M + 1, 72), 354 (23),
338 (41), 252 (100), 204 (16), 165 (24), 154 (42), 136
(37). Anal. Calcd for C22H31N8O4P: C 52.58, H 6.22,
N 22.30, P 6.16. Found: C 52.42, H 6.29, N 22.48, P
6.01.
2-[Dimorpholin-4-yl(2-nitrophenyl)phosphorimi-
doyl]-3-pyrrolidin-1-yl-but-2-enenitrile 6b. Brown
solid (0.47 g, 93%). Mp 98–103◦C. 31P NMR: δ = 18.5.
1H NMR (CDCl3): δ = 1.90–2.06 (bm, 4H, CH2), 2.19
(s, 3H), 3.18–3.38 (m, 8H, PNCH2), 3.41–3.56 (bm,
2H, NCH2), 3.58–3.79 (m, 8H, OCH2), 3.81–3.95 (bm,
3
2H, NCH2), 6.62 (t, JHH = 7.2 Hz, 1H, 4-Ph), 6.79
3
3
(d, JHH = 7.2 Hz, 1H, 6-Ph), 7.18 (td, JHH = 7.2 Hz,
2-[[3-(5-Chloro-2-methoxyphenyl)triaz-2-enylid-
ene](dimorpholin-4-yl)phosphoranyl]-3-pyrrolidin-1-
yl-but-2-enenitrile 5c. Orange solid (1.4 g, 37%). Mp
4 JHH = 1.5 Hz, 1H, 5-Ph), 7.58 (ddd, JHH = 7.2 Hz,
3
4 JHH = 1.5 Hz, JPH = 1.5 Hz, 1H, 3-Ph). 13C NMR
5
145–147◦C. 31P NMR: δ = 44.3. H NMR: δ = 1.96–
1
(CDCl3): δ = 20.8 (C(4)), 24.7 (CH2), 25.8 (CH2),
45.2 (PNCH2), 51.2 (NCH2), 52.8 (NCH2), 58.9
(1 JCP = 167 Hz, C(2)), 67.1 (3 JCP = 7.5 Hz, OCH2),
115.6 (C(4ꢁ)), 121.4 (2 JCP = 11.3 Hz, CN), 124.5
(3 JCP = 8.8 Hz, C(6ꢁ)), 124.8 (C(5ꢁ)), 132.2 (C(3ꢁ)),
144.2 (2 JCP = 22.6 Hz, C(1ꢁ)), 144.9 (3 JCP = 8.8 Hz,
C(2ꢁ)), 169.0 (2 JCP = 16.3 Hz, C(3)). MS, m/z (%):
474 (M+, 1), 457 (7), 287 (57), 199 (64), 183
(52), 136 (100), 86 (85), 70 (66), 56 (58), 42 (42).
Anal. Calcd for C22H31N6O4P: C 55.69, H 6.59, N
17.71, P 6.53. Found: C 55.75, H 6.40, N 17.32,
P 6.35.
2.14 (m, 4H, CH2), 2.25 (s, 3H), 3.19–3.40 (m,
3
8H, PNCH2), 3.54 (t, JHH = 6.9 Hz, 2H, NCH2),
3.65–3.75 (m, 8H, OCH2), 3.86 (s, 1H, OCH3), 3.94
3
3
(t, JHH = 6.9 Hz, 2H, NCH2), 6.85 (d, JHH = 8.7 Hz,
1H, 3-Ph), 7.06 (dd, 3 JHH = 8.7 Hz, 4 JHH = 3.0 Hz, 1H,
4-Ph), 7.15 (d, JHH = 3.0 Hz, 1H, 6-Ph). 13C NMR
4
(CDCl3): δ = 23.5 (C(4)), 24.7 (CH2), 25.7 (CH2), 45.2
(PNCH2), 51.5 (NCH2), 53.2 (NCH2), 55.9 (OCH3),
56.3 (1 JCP = 162 Hz, C(2)), 66.9 (3 JCP = 4.3 Hz, OCH2),
113.0 (C(3ꢁ)), 116.4 (C(4ꢁ)), 120.6 (2 JCP = 8.8 Hz, CN),
125.2 (C(6ꢁ)), 125.4 (C(5ꢁ)), 142.4 (C(1ꢁ)), 152.2
(C(2ꢁ)), 169.8 (2 JCP = 17.6 Hz, C(3)). MS FAB,
m/z (%): 522 (M + 1, 25), 494 (56), 354 (19), 338
(32), 252 (100), 204 (17), 169 (13), 165 (32), 154 (13),
136 (16). Anal. Calcd for C23H33ClN7O3P: C 52.92,
H 6.37, N 18.78, P 5.93. Found: C 52.64, H 6.43, N
18.60, P 5.73.
2-[(5-Chloro-2-methoxyphenyl)(dimorpholin-4-yl)-
phosphorimidoyl]-3-pyrrolidin-1-yl-but-2-enenitrile
6c. Yellow solid (0.45 g, 95%). Mp 75–80◦C. 31P
NMR: δ = 17.0. 1H NMR: δ = 1.93–2.05 (bm, 4H,
CH2), 2.11 (s, 3H), 3.21–3.37 (m, 8H, PNCH2),
Heteroatom Chemistry DOI 10.1002/hc

200 Kostyuk et al.
3.40 (m, 15H, NCH2 (4H), OCH2 (8H), OCH3
(3H)), 6.60 (s, 2H), 6.66 (s, 1H). 13C NMR (CDCl3):
δ = 21.4 (C(4)), 25.3 (b, CH2), 45.5 (PNCH2), 52.0 (b,
NCH2), 55.7 (OCH3), 60.2 (1 JCP = 173 Hz, C(2)), 67.1
(3 JCP = 5 Hz, OCH2), 111.5 (C(3ꢁ)), 117.2 (C(4ꢁ)), 121.6
(2 JCP = 10.1 Hz, CN), 123.0 (3 JCP = 8.8 Hz, C(6ꢁ)),
125.0 (C(5ꢁ)), 141.2 (C(1ꢁ)), 152.2 (3 JCP = 16.3 Hz,
C(2ꢁ)), 169.0 (2 JCP = 15.1 Hz, C(3)). MS, m/z (%): 493
(M+, 17), 323 (68), 252 (100), 203 (15), 183 (26), 167
(76), 165 (54), 157 (43), 118 (21), 86 (44), 70 (14),
56 (26), 42 (15). Anal. Calcd for C23H33ClN5O3P: C
55.92, H 6.73, N 14.18, P 6.27. Found: C 55.61, H
6.44, N 14.01, P 6.03.
added and stirred until complete dissolution, ca.12
h. The reaction mixture was washed with water
and was dried over Na2SO4, and the solvent was
evaporated in vacuo. The residue was recrystallized
from i-PrOH. Yellow crystals. (1.8 g, 41%). Mp
130–135◦C. 31P NMR: δ = 63.8. 1H NMR (CDCl3):
2
δ = 1.95 (3H, d, JPH = 13.2, PCH3), 2.03 (4H, bm,
CH2), 2.46 (3H, s, CH3), 3.09–3.31 (4H, m, PNCH2),
3.54 (2H, bm, NCH2), 3.66 (4H, t, 3 JHH = 4.2, OCH2),
3.90 (2H, bm, NCH2). 13C NMR (CDCl3): δ = 20.8
(C(4)), 21.5 (1 JCP = 78.1, PCH3), 24.4 (b, CH2), 25.4
(b, CH2), 44.5 (PNCH2), 51.0 (b, NCH2), 51.9 (b,
NCH2), 65.0 (1 JCP = 124, C(2)), 67.0 (3 JCP = 8.1,
OCH2), 121.4 (2 JCP = 13.8, CN), 167.3 (2 JCP = 12.8,
C(3)). MS, m/z (%): 299 (M+, 50), 214 (99), 213 (48),
199 (100), 181 (81), 136 (61), 135 (64), 87 (53), 69
(73), 42 (45). Anal. Calcd for C13H22N3OPS: C 52.16,
H 7.41, N 14.04, P 10.35, S 10.71. Found: C 52.01, H
7.12, N 13.85, P 10.511, S 10.42.
O,O-Diethyl 1-cyano-2-pyrrolidin-1-yl-prop-1-
enylphosphonothioate 7
To a stirred solution of PCl3 (1.01 g, 7.3 mmol)
in benzene (20 mL) under dry argon, a solution
of enamine 1a (1 g, 7.3 mmol) and Et3N (0.96 g,
9.5 mmol) in benzene (20 mL) was added dropwise.
After 20 h, a solution of ethanol (0.67 g, 14.6 mmol)
and Et3N (1.48 g, 14.6 mmol) in benzene (20 mL) was
added dropwise, and in 20 min finely ground sulfur
(0.23 g, 7.3 mmol) was added. After 1 h, the reaction
mixture was washed with water. The organic phase
was separated, dried (Na2SO4), and evaporated in
vacuo; the residue was recrystallized from cyclo-
2-[Methyl(morpholin-4-yl)(4-nitrophenyl)-
phosphorimidoyl]-3-pyrrolidin-1-yl-but-2-
enenitrile 9b
To a solution of MePCl2 (0.43 g, 3.7 mmol) in
benzene (20 mL), a solution of 1a (0.5 g, 3.7 mmol)
and Et3N (0.48 g, 4.8 mmol) in benzene (20 mL)
was added dropwise with stirring. After 18 h,
p-nitrophenylazide (0.61 g, 3.7 mmol) was added
and after 30 min when the evolution of nitrogen
stopped a solution of morpholine (0.32 g, 3.7 mmol)
and Et3N (0.37 g, 3.7 mmol) in benzene (20 mL) was
added dropwise with stirring. After 1 h, the reaction
mixture was washed with water. The organic layer
was separated, dried over Na2SO4, and evapo-
rated in vacuo. The residue was crystallized from
i-PrOH. Orange amorphous crystals (0.3 g, 20%).
31P NMR: δ = 24.4. 1H NMR (CDCl3): δ = 1.82 (d,
2 JPH = 13.2 Hz, 3H, PCH3), 1.89–2.11 (bm, 4H, CH2),
2.25 (s, 3H, CH3), 3.18–3.34 (bm, 4H, PNCH2), 3.40–
3.58 (bm, 2H, NCH2), 3.63–3.78 (bm, 4H, OCH2),
hexane. Yellow solid (0.53 g, 25%). Mp 89–92◦C. 31
P
1
NMR: δ = 84.6. H NMR (C6D6): δ = 0.87–1.03 (bm,
3
4H, CH2), 1.2 (t, JHH = 7 Hz, 6H, POCH2CH3), 2.03
(s, 3H, CH3), 2.19–2.35 (bm, 2H, NCH2), 3.39–3.61
(bm, 2H, NCH2), 4.12–4.38 (m, 4H, POCH2CH3). 13
C
NMR (CDCl3): δ = 16.0 (3 JCP = 7.5 Hz, POCH2CH3),
21.2 (C(4)), 24.7 (CH2), 25.8 (CH2), 51.3 (NCH2),
52.2 (NCH2), 63.1 (2 JCP = 6.3 Hz, POCH2CH3), 69.9
(1 JCP = 184 Hz, C(2)), 120.2 (2 JCP = 11.3 Hz, CN),
166.6 (2 JCP = 18.9 Hz, C(3)). MS, m/z (%): 288 (M+,
49), 244 (32), 215 (100), 199 (19), 183 (22), 167 (12),
135 (43), 108 (10), 93 (16), 70 (41), 42 (20). Anal.
Calcd for C12H21N2O2PS: C 49.99, H 7.34, N 9.72,
P 10.74, S 11.12. Found: C 49.78, H 7.37, N 9.51, P
10.47, S 10.91.
3
3.84–4.07 (bm, 2H, NCH2), 6.71 (d, JHH = 8.1 Hz,
3
2H, 2-Ph), 8.00 (d, JHH = 8.1 Hz, 2H, 3-Ph). 13C
NMR (CDCl3): δ = 13.5 (1 JCP = 90.5 Hz, PCH3) 20.4
(C(4)), 24.7 (CH2), 25.8 (CH2), 44.3 (PNCH2), 51.4
(NCH2), 52.5 (NCH2), 60.6 (1 JCP = 126 Hz, C(2)),
67.1 (3 JCP = 7.5 Hz, OCH2), 121.6 (2 JCP = 20.1 Hz,
CN), 125.8 (3 JCP = 2.5 Hz, C(2ꢁ)), 128.3 (C(3ꢁ)), 137.9
(C(1ꢁ)), 159.3 (C(4ꢁ)), 167.5 (2 JCP = 13.8 Hz, C(3)).
MS, m/z (%): 403 (M+, 5), 318 (40), 303 (79), 181
(100), 136 (16), 132 (36), 86 (23), 70 (19), 56 (10), 42
(13). Anal. Calcd for C19H26N5O3P: C 56.57, H 6.50,
N 17.36, P 7.68. Found: C 56.61, H 6.37, N 17.11,
P 7.52.
2-[Methyl(morpholin-4-ylthiophosphoroyl]-3-
pyrrolidin-1-yl-but-2-enenitrile 9a
To a solution of MePCl2 (1.71 g, 14.7 mmol) in
dichloromethane (20 mL), a solution of enamine 1a
(2 g, 14.7 mmol) and Et3N (1.93 g, 19 mmol) in
dichloromethane (30 mL) was added dropwise
with stirring. In 2 h, a solution of morpholine
(1.28 g, 14.6 mmol) and Et3N (1.48 g, 14.6 mmol)
in dichloromethane (20 mL) was added. After 1
h, finely ground sulfur (0.47 g, 14.7 mmol) was
Heteroatom Chemistry DOI 10.1002/hc

Phosphorylation of Derivatives of β-Dialkyaminocrotonitriles with Phosphorus(III) Halides 201
I. V.; Trostyanskaya, I. G.; Kazankova, M. A. J Gen
2-[Morpholin-4-yl(phenyl)phosphoryl]-3-
pyrrolidin-1-yl-but-2-enenitrile 11
Chem USSR 1989 59, 1686–1687 (Engl. Transl.);
(d) Kazankova, M. A.; Trostyanskaya, I. G.; Efimova,
I. V.; Beletskaya, I. P. Russ J Org Chem 1996, 32(11),
1606–1619.
To a stirred solution of PhPCl2 (1.31 g, 7.3 mmol) in
CH2Cl2 (20 mL) under dry argon, a solution of enam-
ine 1a (1 g, 7.3 mmol) and Et3N (0.88 g, 8.8 mmol)
in CH2Cl2 (20 mL) was added dropwise. After 1 h, to
the stirred solution obtained, a solution of morpho-
line (0.64 g, 7.3 mmol) and Et3N (0.74 g, 7.3 mmol)
in CH2Cl2 (20 mL) was added dropwise. After
0.5 h, finely powered H2O2·H2NC(O)NH2 (0.69 g,
7.3 mmol) was added. After 2 h, the reaction mixture
was washed with water. The organic phase was sepa-
rated, dried (Na2SO4), and evaporated in vacuo. The
residue is a light brown solid (1.98 g, 78%). Mp 103–
105◦C. 31P NMR: δ = 30.0. 1H NMR (CDCl3): δ = 1.90–
2.05 (bm, 4H, CH2), 2.29 (s, 3H), 3.07–3.24 (m,
4H, PNCH2), 3.39–3.56 (bm, 2H, NCH2), 3.58–3.73
(bm, 4H, OCH2), 3.75–3.98 (bm, 2H, NCH2), 7.42–
7.54 (m, 3H, Ph), 7.85–7.97 (m, 2H, oPh). 13C NMR
(DMSOd6): δ = 20.5 (2 JCP = 11.3 Hz, C(4)), 24.6 (CH2),
25.5 (CH2), 44.6 (PNCH2), 50.8 (NCH2), 52.4 (NCH2),
63.7 (1 JCP = 153 Hz, C(2)), 66.9 (3 JCP = 6.3 Hz, OCH2),
121.4 (2 JCP = 9.9 Hz, CN), 128.3 (Ph), 131.5 (Ph),
131.7 (3 JCP = 10.1 Hz, Ph), 132.5 (1 JCP = 133 Hz,
Ph), 168.9 (2 JCP = 16.3 Hz, C(3)). Anal. Calcd for
C18H24N3O2P: C 62.60, H 7.00, N 12.17, P 8.97.
Found: C 62.71, H 6.85, N 11.94, P 8.61.
[3] (a) Tolmachev, A. A.; Merkulov, A. S.; Yurchenko,
A. A.; Semenova, M. G.; Pinchuk, A. M. Russ Chem
B l 1998, 47(9), 1749–1754; (b) Tolmachev, A. A.;
Potikha, L. M.; Yurchenko, A. A.; Kozlov, E. S.;
Pinchuk, A. M. J Gen Chem USSR 1991, 61(10), 2189–
2190 (Engl. Transl.).
[4] (a) Tolmachev, A. A.; Kostyuk, A. N.; Kozlov, E. S.;
Chernega, A. N.; Pinchuk, A. M. Heteroatom Chem
1992, 3, 163–176; (b) Kostyuk, A. N.; Lysenko, N. V.;
Marchenko, A. P.; Koidan, G. N.; Pinchuk, A. M.;
Tolmachev, A. A. Phosphorus Sulfur Silicon Re-
lat Elem 1998, 139, 209–229; (c) Kostyuk, A. N.;
Volochnyuk, D. M.; Lupiha, L. N.; Pinchuk, A. M.;
Tolmachev, A. A. Tetrahedron Lett 2002, 43, 5423–
5425; (d) Kostyuk, A. N.; Svyaschenko, Y. V.;
Volochnyuk, D. M.; Lysenko, N. V.; Tolmachev, A. A.;
Pinchuk, A. M. Tetrahedron Lett 2003, 44, 6487–
6491.
[5] Lazukina, L. A.; Kuhar, V. P.; Pesotskaya, G. V. Zh
Org Khim 1974, 44, 10, 2355–2356.
[6] Weingarten, H. J Org Chem 1970, 35(11), 3970–3971.
[7] Kostyuk, A. N.; Svyaschenko, Y. V.; Volochnyuk,
D. M.; Lysenko, N. V.; Tolmachev, A. A. Pinchuk,
A. M. Tetrahedron Lett 2003, 44, 6487–6491.
[8] (a) Kozlov, V. A.; Churusova, S. G.; Ivanchenko,
V. I.; Negrebetskii, V. V.; Grapov, A. F.; Mel’nikov,
N. N. J Gen Chem USSR 1986, 56(9), 1775–1778.
(Engl. Transl); (b) Aboujaoude, E. E.; Collignon, N.;
Savignac, P. Phosphorus Sulfur Silicon Relat Elem
1987, 31, 231–244.
[9] Sauve, G.; Berre, N. L.; Zacharie, B. Tetrahedron Lett
1988, 29(19), 2299–2302.
[10] (a) Svyaschenko, Y. V.; Kostyuk, A. N.; Barnych,
B. B.; Volochnyuk, D. M. Tetrahedron 2007, 63(25),
5656–5664; (b) Kostyuk, A. N.; Svyaschenko, Y. V.;
Volochnyuk, D. M. Tetrahedron 2005, 61(39), 9263–
9272.
[11] (a) Hickmott, P. W.; Sheppard, G. J Chem Soc (C)
1971, 1358; (b) Dedina, J.; Kuthan, J.; Palecek, J.;
Schraml, J. Collect Czech Chem Commun 1975, 40,
3476.
REFERENCES
[1] The Chemistry of Enamines, Saul Patai series;
Rappoport, Z (Ed.); Wiley: Hoboken, NJ, 1994.
Published online: July 14, 2004.
[2] (a) Trostyanskaya, I. G.; Efimova, I. V.; Kazankova,
M. A.; Lutsenko, I. F. J Gen Chem USSR 1983,
53(1), 207–208 (Engl. Transl.); (b) Mikhailov, G. Yu.;
Trostyanskaya, I. G.; Kazankova, M. A.; Lutsenko,
I. F. J Gen Chem USSR 1985, 55(7), 1462–1463
(Engl. Transl.); (c) Mikhailov, G. Yu.; Efimova,
Heteroatom Chemistry DOI 10.1002/hc