Addition of secondary amines to alkynylphosphonates

Article abstract of DOI:10.1016/S0040-4039(01)00711-0

Addition of secondary amines to alkynylphosphonates catalyzed by Cu(I) salts proceeds regio- and stereospecifically to form (E)-2-(dialkylamino)alkenylphosphonates. The E-configuration was proved by analysis of ¹³C-³¹P vicinal spin-spin coupling constants in the NMR spectra of the products and authentic model compounds. The ³J_PC constants in the model compounds fall in the range of 6-12 Hz for the cis arrangement of the coupled nuclei and are equal to or higher than 16 Hz for the trans configuration. Related coupling constants in the addition products are around 5 Hz, that is, corresponding to cis coupling.

Full text of DOI:10.1016/S0040-4039(01)00711-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4365–4368
Addition of secondary amines to alkynylphosphonates
Anna E. Panarina, Alla V. Dogadina, Valentin I. Zakharov and Boris I. Ionin*
Laboratory of Organophosphorus Chemistry, Organic Chemistry Department,
St. Petersburg State Technological Institute (Technical University), 26 Moskovskii Prospect, St. Petersburg 198013, Russia
Received 29 November 2000; revised 10 April 2001; accepted 27 April 2001
Abstract—Addition of secondary amines to alkynylphosphonates catalyzed by Cu(I) salts proceeds regio- and stereospecifically to
form (E)-2-(dialkylamino)alkenylphosphonates. The E-configuration was proved by analysis of 13C–31P vicinal spin–spin coupling
3
constants in the NMR spectra of the products and authentic model compounds. The JPC constants in the model compounds fall
in the range of 6–12 Hz for the cis arrangement of the coupled nuclei and are equal to or higher than 16 Hz for the trans
configuration. Related coupling constants in the addition products are around 5 Hz, that is, corresponding to cis coupling. © 2001
Elsevier Science Ltd. All rights reserved.
2-Dialkylaminoalkenylphosphonates can be regarded as
precursors of b-aldo- and b-ketophosphonates.1 They
are also interesting as models of push–pull alkenes for
both chemical and biochemical investigations.2
Recently, a synthetic route to such compounds was
developed by Kazankova, Beletskaya and co-workers3
who prepared diethyl 2-phenyl-2-piperidylethenephos-
phonate by cross-coupling of the corresponding 2-
bromo-1-piperidylstyrene with triethyl phosphite in the
presence of NiBr2 in 55% yield. Herein, we report on a
convenient route to 2-dialkylaminoalkenylphospho-
nates based on the addition of amines to the triple bond
of acetylenic phosphonates.
In 1963 Saunders and Simpson prepared (E)-2-diethyl-
aminoethenephosphonate by reaction of diethylamine
with ethynylphosphonate. The reaction is exothermic
and results in a high yield of the product.4 More
recently, Acheson and co-workers noted5 that
ethynylphosphonate reacts with secondary amines to
form mixtures of E and Z isomers. Propynylphospho-
nate adds secondary amines to form 2-dialkylamino-1-
propenylphosphonates in poor yield (10–15%)
contaminated with 2,2-bis(dialkylamino)propanyl-
phosphonate.6 Addition of primary and secondary
amines to ethynyldiphenylphosphine oxide in the pres-
ence of butyllithium was studied in detail, and was
Table 1. b-Enaminophosphonates 3 (E)-(EtO)2P(O)CHꢀC(NR2 )R1a
2
No.
R1
NR2
Reaction conditions
Method
Time (h)
Yield (%)b
Bp (mmHg)
2
1
2
3
4
5
6
7
8
H
H
H
NEt2
3a
3b
3c
3d
3e
3f
3g
3h
3i
EtOH
MeOH
MeOH
A
B
B
A
B
B
A
B
A
B
B
0.5
12
18
2.5
22
26
9.3
26.5
3.5
50
42
36
80
38
41
45
36
35
41
40
38
109 (0.1)c
112 (0.1)
163 (0.5)
126 (0.1)
170 (0.5)
180 (0.5)
130 (0.1)
156 (0.25)
156 (0.1)
160 (0.1)
165 (0.1)
N(CH2)5
N(CH2)4O
NEt2
N(CH2)5
N(CH2)4O
NEt2
N(CH2)5
NEt2
N(CH2)5
N(CH2)4O
CH3
CH3
CH3
C2H5
C2H5
C6H5
C6H5
C6H5
EtOH, Cu(I)Cl
MeOH, Cu(I)Cl
MeOH, Cu(I)Cl
Et2O, Cu(I)Cl
MeOH, Cu(I)Cl
EtOH, Cu(I)Cl
MeOH, Cu(I)Cl
MeOH, Cu(I)Cl
9
10
11
3j
3k
57
a All products gave satisfactory 1H, 31P, 13C NMR and IR spectra.
b All products were initially formed quantitatively, but partially hydrolyzed into the ketone and decomposed during the isolation process.
c 13C and 31P NMR and IR spectra of the product agree with the published data.5
* Corresponding author. E-mail: bi@thesa.ru
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00711-0

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A. E. Panarina et al. / Tetrahedron Letters 42 (2001) 4365–4368
shown to lead to the corresponding (E)-2-amino-
vinyldiphenylphosphine oxides.7 Non-catalyzed addition
of primary amines to other alkynyldiphenylphosphine
oxides results in the formation of mixtures of E and Z
isomers.8
Establishing the geometric configuration of the 2-dialkyl-
aminoalkenephosphonates 3 is difficult and was not
ascertained earlier.3,10 For elucidation of the configura-
tion of enaminophosphonates 3, we used the well-known
steric dependence of the vicinal spin–spin coupling con-
3
stant. The angular dependence of J coupling was first
We found that addition of secondary amines to
alkynylphosphonates proceeds much better in the pres-
ence of a Cu(I) salt. Rousselet and co-workers noted
earlier9 that addition of primary and secondary amines
to nitriles in the presence of Cu(I) salts proceeds to give
high yields (80–100%) of the addition compounds.
established for H–H pairs11 and confirmed, in part, by
1
our investigations for H–31P12 and 31P–31P13 couplings.
However, steric variations of 3J coupling for the 31P–13C
pair, which could be useful in our case, has scarcely been
studied.14,15
Therefore, we performed the synthesis and study of the
13C NMR spectra of several model compounds with
rigorously defined structures.
With diethyl ethynylphosphonate, addition of secondary
amines both in the presence and absence of Cu(I) salts
proceeds as a cis-addition and leads to E isomers of the
corresponding 2-dialkylaminoethenephosphonates, in
agreement with the data published by Acheson and
co-workers.5 With less reactive substituted ethynylphos-
phonates 1, the reaction in the absence of Cu(I) catalyst
does not occur at a noticeable rate even on heating the
reactants in an ampoule to 120°C. A catalytic amount of
Cu(I) salt allows the addition to proceed regio- and
A comparison of the NMR parameters of the b-enam-
inophosphonates obtained and certain model com-
pounds (Table 2), together with the use of the well-known
appearance of 3J constants in alkenes, which is normally
greater in trans derivatives,16 allowed the unambiguous
assignment of the E configuration (cis addition of amine)
for the compounds 3.
stereospecifically,
affording
(E)-2-(dialkylamino)-
ethenylphosphonates (Table 1). The reaction was carried
out in a polar solvent, such as EtOH, MeOH, or Et2O,
which have been noted to increase the reaction rate in
the cases alkynylphosphine oxides8 and nitriles.9
Additionally, we proved the structures by 1H NMR
experiments with lanthanide shift reagents. For the
b-enaminophosphonates obtained from propynylphos-
phonate we succeeded in identifying the allylic spin–spin
Table 2. Parameters of 13C NMR spectra of model compounds and b-enaminophosphonates 3 (C2H5O)2P(O)CHꢀC(X)R1
No.
R1
X
Isomer
Chemical shifts (ppm)
Spin–spin coupling constants (Hz)
(C2H5O)2P(O)C1HꢀC2(X)(R1)3
l1
l2
l3
1JPC
2JPC
3JPC
6.54 (Z)
1
Me
Me
–
111.71
158.36
20.17 (Z)
189.48
10.7
27.25 (E)
19.43
15.56
29.9
134.50
134.28
136.62
33.33
33.69
40.66
41.30
–
24.21 (E)
23.77
10.37
19.3
23.67
7.0
16.4
6.24
20.08
12.53
14.90
–
2
Me
Me
Me
Ph
Ph
Ph
t-Bu
t-Bu
t-Bu
t-Bu
H
H
H
Cl
H
H
Cl
H
H
E
Z
Z
E
Z
Z
Z
E
Z
Z
E
E
E
E
E
E
E
E
E
E
116.34
116.80
122.32
113.46
115.54
112.67
113.26
110.97
111.51
119.36
72.44
75.50
72.97
76.02
79.19
72.54
75.63
76.60
81.19
148.85
148.62
154.80
147.73
147.29
149.57
161.22
161.92
163.24
167.38
153.48
153.62
158.75
160.06
160.64
164.43
165.99
161.18
164.05
163.77
188.58
188.68
175.32
191.55
184.16
199.05
186.21
188.01
196.88
160.54
209.2
201.31
217.34
212.7
212.9
217.33
215.7
4.97
5.00
6.04
6.7
5.86
3.17
4.73
3.52
2.5
7.54
20.1
19.32
21.0
19.33
19.17
21.6
21.72
17.1
17.36
16.31
3
4a
5
6
7
8
9
10
11a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
Cl
Cl
N(CH2)5
N[(CH2)2]O
NEt2
N(CH2)5
N[(CH2)2]O
NEt2
N(CH2)5
NEt2
N(CH2)5
N[(CH2)2]O
H
–
–
5.0
Me
Me
Me
Et
Et
Ph
17.15
17.42
16.95
22.33
23.46
135.2
136.45
135.24
3.57
2.82
5.1
5.18
5.6
217.82
214.4
212.6
Ph
Ph
4.07
4.07
83.93
a Phosphonic dichloride.

A. E. Panarina et al. / Tetrahedron Letters 42 (2001) 4365–4368
4367
4
coupling constant JHP, which was found to be equal to
3JHH=14.8 Hz, 3JHP=14.8 Hz, CH); 13C NMR (50
MHz): 16.27 (CH3), 42.9 (CH2-N), 60.88 (CH2-O), 65.97
(CH2-O, morph.), 75.5 (d, 1JPC=201.31 Hz, CH), 153.62
1.5 Hz. This value corresponds to the cisoid allylic
coupling, while the corresponding transoid constant has
been determined in the range 0–0.5 Hz.12
2
(d, JPC=19.32 Hz, ꢀCꢁN); 31P NMR (80 MHz): 27.59;
IR (KBr): 2970, 1600, 1200, 1020 cm−1.
We also found that the required b-(dialkyl-
amino)alkenylphosphonates can also be prepared from
the corresponding b-chloroalkenylphosphonates 4, the
(E)-Diethyl-2-N-diethylaminoprop-1-enylphosphonate
(3d): mp 126°C (0.1 mmHg); 1H NMR (200 MHz): 0.84
4
same
E
isomers being obtained. However,
(t, 6H, CH3), 1.01 (t, 6H, CH3), 1.92 (d, 3H, JHP=1.6
Hz, CH3), 2.95 (q, 4H, CH2-N), 3.46 (d, 1H, 2JHP=9.81
Hz, CH), 3.71 (q, 4H, CH2-O); 13C NMR (50 MHz):
12.66 (CH3), 16.31 (CH3), 17.15 (d, 3JPC=5.0 Hz, CH3),
the chloroalkenylphosphonates initially eliminate
hydrogen chloride to form acetylenic compounds 1,
which add amine 2 in the second step. Formation
of acetylenes was monitored by 1H NMR spectro-
scopy.
1
43.79 (CH2-N), 60.45 (CH2-O), 72.97 (d, JPC=217.34
Hz, CH), 158.75 (d, 2JPC=21.0 Hz, ꢀCꢁN); 31P NMR (80
(RO)2P(O)CHꢀCClR1+R2 NH“[(RO)2P(O)CꢂCR1]“(E)-(RO)2P(O)CHꢀC(NR2 )R1R=Et;
2
2
4
1
1
3d,i
R1=Me; R2=Et
The b-(dialkylamino)alkenylphosphonates obtained are
easily hydrolyzed with water to form b-ketophospho-
nates 5. The latter are interesting as reagents for Horner–
Emmons synthesis1 and also are known as effective metal
extractors.17
MHz): 27.46; IR (KBr): 2970, 1558, 1213, 1029
cm−1.
(E)-Diethyl-2-piperidinoprop-1-enylphosphonate (3e): mp
1
170°C (0.5 mmHg); H NMR (200 MHz): 1.1 (t, 6H,
(RO)2P(O)CHꢀC(NR2 )R1+H2O“(RO)2P(O)CHꢁC(ꢀO)R1
2
3a-k
5a-k
4
CH3), 1.38 (m, 6H, CH2 piper.), 1.98 (d, 3H, JHP=1.0
Experimental
2
Hz, CH3), 3.02 (t, 4H, CH2-N), 3.87 (d, 1H, JHP=9.75
Hz, CH), 3.88 (q, 4H, CH2-O); 13C NMR (50 MHz): 15.8
General procedure for the preparation of 2-(dialkyl-
amino)alkenylphosphonates 3. Method A. A 20 ml flask
equipped with a reflux condenser and magnetic stirrer
was purged with dry argon and the corresponding solvent
(10 ml), alkynylphosphonate 1 (8.5 mmol) and amine (9.4
mmol) were added, and in some cases Cu(I)Cl 50 mg was
added as a catalyst. The reaction mixture was stirred
under reflux for several hours and monitored by 1H
NMR spectroscopy. After completion of the reaction, the
mixture was filtered to separate the catalyst, the solvent
was removed in vacuo and the residue was distilled in a
vacuum at 0.1 mmHg. Method B. Alkynylphosphonate
(8.5 mmol) and amine (9.4 mmol) were sealed in an
ampoule with 2 ml of methanol and, in some experi-
ments, with 50 mg of Cu(I)Cl catalyst. The mixture was
heated on a bath for several hours at 100–110°C. Then
the product was isolated by distillation in a vacuum (see
Table 1).
3
(CH3), 17.42 (d, JPC=3.57 Hz, CH3), 23.65 (p-CH2,
piper.), 24.7 (m-CH2, piper), 46.69 (CH2-N), 60.11 (CH2-
1
2
O), 76.02 (d, JPC=212.7 Hz, CH), 160.06 (d, JPC
=
19.33 Hz, ꢀCꢁN); 31P NMR (80 MHz): 27.85; IR (KBr):
2970, 1560, 1220, 1029 cm−1.
(E)-Diethyl-2-morpholinoprop-1-enylphosphonate
(3f):
mp 180°C (0.5 mmHg); 1H NMR (200 MHz): 1.12 (t, 6H,
4
CH3), 2.02 (d, 3H, JHP=2.0 Hz, CH3), 2.98 (t, 4H,
2
CH2-N), 3.53 (t, 4H, CH2-O), 3.8 (d, 1H, JHP=9.0 Hz,
CH), 3.85 (q, 4H, CH2-O); 13C NMR (50 MHz): 15.8
3
(CH3), 16.95 (d, JPC=2.82 Hz, CH3), 45.7 (CH2-N),
60.29 (CH2-O), 65.71 (CH2-O, morph.), 79.19 (d, 1JPC
=
212.9 Hz, CH), 160.64 (d, JPC=19.17 Hz, ꢀCꢁN); 31P
NMR (80 MHz): 26.04; IR (KBr): 2970, 1560, 1213, 1024
cm−1.
2
(E)-Diethyl-2-N-diethylaminobut-1-enylphosphonate
(3g): mp 130°C (0.1 mmHg); 1H NMR (200 MHz): 0.90
(t, 6H, CH3), 0.93 (t, 3H, CH3), 1.07 (t, 6H, CH3), 2.4
(q, 2H, CH2), 3.0 (q, 4H, CH2-N), 3.48 (d, 1H, 2JHP=9.8
Hz, CH), 3.79 (q, 4H, CH2-O); 13C NMR (50 MHz):
12.91 (CH3), 13.96 (CH3, Et), 16.37 (CH3), 22.33 (d,
3JPC=5.1 Hz, CH2, Et), 43.3 (CH2-N), 60.45 (CH2-O),
72.54 (d, JPC=217.33 Hz, CH), 164.43 (d, JPC=21.6
Hz, ꢀCꢁN); 31P NMR (80 MHz): 27.17; IR (KBr): 2970,
1546, 1213, 1029 cm−1.
(E)-Diethyl-2-piperidinoeth-1-enylphosphonate (3b): mp
1
112°C (0.1 mmHg); H NMR (200 MHz): 1.28 (t, 6H,
CH3), 1.54 (m, 6H, CH2 piper.), 3.11 (t, 4H, CH2-N), 3.97
2
(q, 4H, CH2-O), 4.14 (d, 1H, JHP=6 Hz, CH), 6.93 (t,
1H, 3JHH=14.5 Hz, 3JHP=15.25 Hz, CH); 13C NMR (50
MHz): 15.92 (CH3), 23.83 (p-CH2, piper.), 24.27 (m-CH2,
1
2
1
piper), 48.75 (CH2-N), 60.33 (CH2-O), 72.44 (d, JPC
=
209.2 Hz, CH), 153.44 (d, JPC=20.1 Hz, ꢀCꢁN); 31P
2
NMR (80 MHz): 29.45.
(E)-Diethyl-2-morpholinoeth-1-enylphosphonate (3c): mp
(E)-Diethyl-2-piperidinobut-1-enylphosphonate (3h): mp
1
1
163°C (0.5 mmHg); H NMR (200 MHz): 1.53 (t, 6H,
156°C (0.25 mmHg); H NMR (200 MHz): 1.21 (t, 6H,
CH3), 3.08 (t, 4H, CH2-N), 3.61 (t, 4H, CH2-O), 3.94 (q,
CH3), 1.25 (t, 3H, CH3), 1.5 (m, 6H, CH2 piper.), 2.57
(q, 2H, CH2, Et), 3.08 (m, 4H, CH2-N), 3.85 (d, 1H,
4H, CH2-O), 4.18 (d, 1H, 2JHP=12 Hz, CH), 6.9 (t, 1H,

4368
A. E. Panarina et al. / Tetrahedron Letters 42 (2001) 4365–4368
2JHP=10.3 Hz, CH), 3.93 (q, 4H, CH2-O); 13C NMR
163.77 (d, 2JPC=16.31 Hz, ꢀCꢁN); 31P NMR (80 MHz):
3
23.12; IR (KBr): 2970, 1540, 1220, 1020 cm−1.
(50 MHz): 13.02 (CH3), 16.77 (CH3), 23.46 (d, JPC
=
5.18 Hz, CH3), 25.14 (CH2, piper), 47.07 (CH2-N),
1
60.39 (CH2-O), 75.63 (d, JPC=215.7 Hz, CH), 165.99
2
(d, JPC=21.72 Hz, ꢀCꢁN); 31P NMR (80 MHz): 27.25;
References
IR (KBr): 2973, 1629, 1233, 1013 cm−1.
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(E)-Diethyl-2-N-diethylaminophenyleth-1-enylphospho-
1
nate (3i): mp 156°C (0.1 mmHg); H NMR (200 MHz):
0.75 (m, 12H, CH3), 2.28 (q, 4H, CH2-N), 3.42 (q, 4H,
2
CH2-O), 3.87 (d, 1H, JHP=10.3 Hz, CH), 7.0 (m, 5H,
arom.); 13C NMR (50 MHz): 11.7 (CH3), 15.16 (CH3),
42.71 (CH2-N), 59.3 (CH2-O), 76.6 (d, 1JPC=217.82 Hz,
CH), 126.65–127.54 (m, p-CH-arom.), 128.15 (o-CH-
3
arom.), 135.2 (d, JPC=5.6 Hz, C-ipso, arom.), 161.18
2
(d, JPC=17.1 Hz, ꢀCꢁN); 31P NMR (80 MHz): 24.14;
IR (KBr): 2970, 1533, 1200, 1029 cm−1. MS (EI) 310;
m/z (%): 29 (77.9), 72 (51.7), 103 (51.3), 131 (34.4), 174
(100), 282 (29.3), 310 (60.7).
(E)-Diethyl-2-piperidinophenyleth-1-enylphosphonate
1
(3j): mp 160°C (0.1 mmHg); H NMR (200 MHz): 1.06
(t, 6H, CH3), 1.55 (m, 6H, CH2 piper.), 3.0 (m, 4H,
2
CH2-N), 4.11 (q, 4H, CH2-O), 4.36 (d, 1H, JHP=9.8
Hz, CH), 7.35 (m, 5H, arom.); 13C NMR (50 MHz):
15.82 (m-CH2, piper.), 15.85 (CH3), 25.23 (p-CH2,
piper.), 48.62 (o-CH2, piper.), 60.34 (CH2-O), 81.19 (d,
1JPC=214.4 Hz, CH), 127.63 (m-CH-arom.), 128.33
3
10. Kazankova, M. A.; Trostyanskaya, I. G.; Lutsenko, S.
V.; Beletskaya, I. P. Tetrahedron Lett. 1999, 40, 559–572.
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12. Petrov, A. A.; Ionin, B. I.; Ignat’ev, V. M. Tetrahedron
Lett. 1968, 15–16.
(p-CH-arom.), 128.99 (o-CH-arom.), 136.45 (d, JPC
=
4.07 Hz, C-ipso, arom.), 164.05 (d, 2JPC=17.36 Hz,
ꢀCꢁN); 31P NMR (80 MHz): 24.6; IR (KBr): 2970,
1540, 1220, 1029 cm−1.
13. Timofeeva, T. N.; Ignat’ev, V. M.; Ionin, B. I.; Petrov, A.
A. Dokl. Akad. Nauk SSSR 1969, 189, 1052–1054.
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17. Richard, J. J.; Banks, C. V. J. Org. Chem. 1963, 28, 123.
(E)-Diethyl-2-morpholinophenyleth-1-enylphosphonate
(3k): mp 165°C (0.1 mmHg); 1H NMR (200 MHz): 0.97
(t, 6H, CH3), 2.87 (t, 4H, CH2-N), 3.55 (t, 4H, CH2-O,
2
morph.), 3.67 (q, 4H, CH2-O), 4.37 (d, 1H, JHP=9.2
Hz, CH), 7.27 (m, 5H, arom.); 13C NMR (50 MHz):
15.67 (CH3), 47.59 (CH2-N), 60.38 (CH2-O), 65.94
(CH2-O, morph.), 83.93 (d, 1JPC=212.6 Hz, CH),
127.57 (m-CH-arom.), 128.75 (p-CH-arom.), 128.89 (o-
3
CH-arom.), 135.24 (d, JPC=4.07 Hz, C-ipso, arom.),
.