Mendeleev Commun., 2015, 25, 232–233
effective as phosphorus components.12 Taking into consideration
raising its amounts caused dropping the yields of the products.
The use of acetonitrile as a solvent in the case of solid aldehydes
(2,3-dimethoxy- or 2,3,4-trimethoxybenzaldehyde) to ensure
better contact of reagents led to noticeable decrease in the yield.
Finally, in contrast to the above cited work12 where reactions
with morpholine or piperidine were completed in 10–20 min,
significantly longer reaction times were required in the case
of compound 1 to consume entirely starting triethyl phosphite.
Typically, after 20 h of reaction, remaining amounts of P(OEt)3
did not exceed 5%, being even lower in many cases.
that hydrogen chloride and water contained in the starting amine
salt 1 may bring some complications, we initially studied the
outcome of a model reaction between (EtO)2P(O)H and (EtO)3P,
amine 1 and 4-fluorobenzaldehyde (which allows one to perform
19F NMR monitoring of the reaction).
No reaction occurred when equimolar amounts of 4-piperidone
hydrochloride monohydrate, diethyl phosphite and 4-fluorobenz-
aldehyde were treated with 5 mol% of Mg(ClO4)2: within 6 h, the
mixture contained only starting diethyl phosphite (dP 7.3 ppm)
and 4-fluorobenzaldehyde (dF –103.5 ppm). However, on moving
to triethyl phosphite, a mixture of a-(4-fluorophenyl)-a-hydroxy-
methylphosphonate 3a (51 mol%) (dP 20.7 ppm, dF –114.7 ppm)
and the desired amino phosphonate 2a (22 mol%) (dP 21.3 ppm,
dF –114.1 ppm) was obtained. Generally, in the 31P NMR spectra
chemical shifts of a-amino(aryl)methylphosphonates were located
approximately 0.3–0.5 ppm downfield of those of a-hydroxy-
(aryl)methylphosphonates. The reaction mixture also contained
(EtO)3P (2.5 mol%), (EtO)2P(O)H (4.3 mol%), and product
resulting from oxidation and hydrolysis of triethyl phosphite
(8.5 mol%) (dP –1.54 ppm). Other by-products had phosphonate
nature (dP in the range 33.3–22.4 ppm) and were present in small
amounts (11.7 mol% in total).
According to the 31P NMR data, the crude mixtures contained
approximately 42–60% of compounds 2a–f, 15–21% of the above
mentioned admixtures with phosphonate structure, 15–20% of
hydroxy phosphonates 3, and 7–15% of a compound that was a
product of oxidation and/or hydrolysis of P(OEt)3. Final column
chromatography afforded the desired a-amino phosphonates
2a–f in moderate yields (32–51%).
In conclusion, this study has demonstrated that(aryl)(4-oxo-
piperidin-1-yl)methylphosphonates can be obtained in moderate
yields through the Kabachnik–Fields reaction between 4-piperidon
e
hydrochloride monohydrate, an aromatic aldehyde and triethyl
phosphite in the presence of triethylamine and magnesium per-
chlorate as a catalyst.
When triethylamine was introduced to liberate free base from
salt 1 (with molar ratio 1: Et3N being 1:1), different results were
obtained for diethyl and triethyl phosphites. In the case of diethyl
phosphite with equimolar amounts of compound 1, 4-fluorobenz-
aldehyde, Et3N and 5 mol% of Mg(ClO4)2, the Abramov reac-
tion proceeded giving exclusively hydroxymethylphosphonate
This work was supported by the Russian Foundation for Basic
Research (project no. 14-03-00687).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2015.05.026.
6
3a (dP 21.12 ppm, doublet with JPF 4.4 Hz; dF –115.4 ppm,
6
doublet with JFP = 4.8 Hz). The similar reaction with triethyl
phosphite occurred more slowly than the above considered reac-
tions, and after 6 h the mixture consisted of (EtO)3P (27 mol%),
(EtO)2P(O)H (1.5 mol%), a-amino phosphonate 2a (47 mol%),
and corresponding hydroxy phosphonate 3a (15 mol%). The
increase in reaction time from 6 to 24 h caused a decrease in
residual amount of triethyl phosphite down to ~5 mol% with a
slight increase in amounts of phosphonate 2a and a-hydroxy-
methylphosphonate and strong increase in amounts of above
mentioned by-products of phosphonate nature.
Thus, triethylamine was found to be an essential component for
the successful outcome of the synthesis of amino phosphonates 2.
When Et3N was replaced by K2CO3 as a base, only hydroxy
phosphonates 3 were formed. Raising the amounts of P(OEt)3
resulted in growth of the fraction of above by-products containing
C–P(O)(OEt)2 bond.
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Diethyl (4-oxopiperidin-1-yl)(2-thienyl)methylphosphonate 2d: yellowish
viscous liquid, yield 35%. 1H NMR (400 MHz, CDCl3) d: 1.14 and 1.37
(2t, 3H, POCH2Me, JHH 7.0 Hz), 2.46 [t, 4H, N(CH2)2, JHH 5.9 Hz],
2.78–2.85 (m, 2H), 3.19–3.26 (m, 2H, CH2), 3.85–3.95 (m, 1H, 0.5POCH2),
3.99–4.07 (m, 1H, 0.5POCH2), 4.21–4.30 (m, 2H, POCH2), 4.35 (d,
3
3
2
3
3
1H, PCH, JPH 24.4 Hz), 7.02 (dd, 1H, JHH 3.6 Hz, JHH 5.0 Hz), 7.24
(m, 1H), 7.8 (m, 1H). 13C NMR (100 MHz, CDCl3) d: 16.08 and 16.46
(2d, POCH2Me, JPC 5.6 Hz), 41.61 (NCH2CH2), 50.50 (d, NCH2CH2,
3JPC 8.0 Hz), 61.36 (d, PCH, 1JPC 164 Hz), 62.39 and 63.16 (2d, POCH2,
2JPC 7.1 Hz), 125.73 (d, JPC 1.5 Hz), 126.88, 128.44 (d, JPC 6.3 Hz),
133.38 (d, 2JPC 7.3 Hz), 208.06 (C=O). 31P NMR (162 MHz, CDCl3) d:
20.57. Found (%): C, 50.54; H, 7.01; N, 4.25. Calc. for C14H22NO4PS (%):
C, 50.75; H, 6.69; N, 4.23.
3
4
3
For characteristics of compounds 2e,f, see Online Supplementary
Materials.
Received: 4th August 2014; Com. 14/4438
– 233 –