Synthesis of dialkyl {(aryl)[2,2-dimethyl-4-oxo-6-(piperidin-1-yl)-4H-[1,3] dioxin-5-yl]methyl}phosphonate by reaction of Meldrum's acid, aryl aldehydes and trialkyl phosphites in the presence of piperidine

Article abstract of DOI:10.3184/174751913X13701025495780

A four-component reaction between Meldrum's acid, aryl aldehydes with trialkyl phosphites in the presence of piperidine has been developed. The reaction affords dialkyl {(aryl)[2,2-dimethyl-4-oxo-6-(piperidin-1-yl)-4H-[1,3] dioxin-5- yl]methyl}phosphonate in moderate to good yields in a one-pot process.

Full text of DOI:10.3184/174751913X13701025495780

402 RESEARCH PAPER
JULY, 402–403
JOURNAL OF CHEMICAL RESEARCH 2013
Synthesis of dialkyl {(aryl)[2,2-dimethyl-4-oxo-6-(piperidin-1-yl)-4H-
[1,3]dioxin-5-yl]methyl}phosphonate by reaction of Meldrum’s acid,
aryl aldehydes and trialkyl phosphites in the presence of piperidine
Reza Khosravia, Mohammad R. Hosseini-Tabatabaeib* and Ali Forghanihaa
aDepartment of Chemistry, Arak Branch, Islamic Azad University, Arak, Iran
bDepartment of Chemistry, Islamic Azad University, Zahedan Branch, PO Box 98135-978, Zahedan, Iran
A four-component reaction between Meldrum’s acid, aryl aldehydes with trialkyl phosphites in the presence of piper-
idine has been developed. The reaction affords dialkyl {(aryl)[2,2-dimethyl-4-oxo-6-(piperidin-1-yl)-4H-[1,3]dioxin-5-
yl]methyl}phosphonate in moderate to good yields in a one-pot process.
Keywords: four-component reaction, Meldrum’s acid, trialkyl phosphites, aryl aldehydes, piperidine
The development of simple synthetic routes for widely used
organic compounds from readily available reagents is one of
the major tasks in organic synthesis.1 Due to its high acidity
(pKa 7.5)2 and tendency to regenerate ketones or aldehydes,
Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione),3,4
appears to be an attractive reagent in organic synthesis. How-
ever, synthesis applications of this compound have received
little attention except as an alternative for cyclic malonic
esters.5,6 Useful applications of alkylidene derivatives of
Meldrum’s acid as dienophiles in Diels–Alder reactions7 and
Michael acceptors have been reported, showing advantages
of these systems over their acyclic analogues.8,9 Alkylidene
Meldrum’s acids are readily accessible from Meldrum’s
acid and carbonyl compounds (ketones and aldehydes) on a
relatively large scale.10
There have been many studies on the reactions between
trivalent phosphorus nucleophiles and unsaturated carbonyl
compounds in the presence of a proton source such as an alco-
hol.11 There are other recent reports on the reaction between
phosphites and acetylenic esters in the presence of an acidic
organic compound, all of which proceed to products through
a phosphite ylide intermediate.12–14 However, this intermediate
has not been isolated nor characterised in any of these reports
and is usually hydrolysed or rearranged to the corresponding
phosphonates. In the context of our recent studies15–19 on the
reactivity of isopropylidene Meldrum’s acid, we studied the
reaction between Meldrum’s acid, aryl aldehydes with trialkyl
phosphites in the presence of piperidine.
Results and discussion
The reaction of Meldrum’s acid 1 and aryl aldehydes 2 with
trialkyl phosphites 3 in the presence of piperidine 4 leds to
dialkyl {(aryl)[2,2-dimethyl-4-oxo-6-(piperidin-1-yl)-4H-[1,3]-
dioxin-5-yl]methyl}phosphonate 5 in good yields (Scheme 1).
The structure of compounds 5a–e were deduced from their
elemental analyses and their IR, 1H, 13C, and 31P NMR spectra.
A reasonable mechanism for the formation of compound 5
is presented in Scheme 2. Trialkyl phosphite attacks to the
condensation product of meldrum’s acid 1 and aryl aldehyde 6
leds to a diionic intermediate 7. Cyclisation of this zwitterionic
intermediate to produce the oxaphosphorane 8. The attack of
the piperidine on 8 is initiated by conjugate addition to the
double bond and cleavage of the phosphorus–oxygen bond by
nucleophile produced 5.
In summary, we report the four-component reaction between
Meldrum’s acid, aryl aldehydes with trialkyl phosphites in the
presence of piperidine to afford dialkyl {(aryl)[2,2-dimethyl-
4-oxo-6-(piperidin-1-yl)-4H-[1,3]dioxin-5-yl]methyl}phospho-
nate in good yields. This method has the advantage that the
reaction is performed in neutral conditions and the starting
materials can be mixed without any activation nor modification.
Experimental
Elemental analyses were performed using a Costech ECS 4010
CHNS-O analyser. Mass spectra were recorded on a Finnigan-Mat
8430 mass spectrometer operating at an ionisation potential of 70 eV.
Scheme 1 Four-component reaction between Meldrum’s acid and aryl aldehydes with trialkyl phosphites in the presence
of piperidine.
* Correspondent. E-mail: dr_hosseini_tabatabaei@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2013 403
(1H, d, 2JHP = 28 Hz, CH), 7.13 (2H, d, 3JHH = 7 Hz, 2CH aromatic),
3
7.52 (2H, d, JHH = 7 Hz, 2CH aromatic). 13C NMR (100.6 MHz,
1
CDCl3): δ 22.33 (CH2), 25.89 (2CH3), 44.33 (2CH2), 38.16 (d, Jcp
=
140.8 Hz, P-CH), 50.51 and 52.80 (2d, 2JCP = 8 Hz, P(OCH3)2), 53.46
(2CH2), 72.24 (CMe2), 101.52 (d, 2JCP = 36 Hz, C=C), 128.05, 130.74,
3
132.05, and 137.04 (aromatic), 137.04 (=CON), 167.01 (d, JCP
=
6.0 Hz, C=O), 31P NMR (162 MHz, CDCl3): δ 33.14.
Dimethyl {(4-nitrophenyl)-(2,2-dimethyl-4-oxo-6-piperidin-1-yl-
4H-[1,3]dioxin-5-yl)methyl}phosphonate (5d): Yield: 92%; Yellow
oil. IR (KBr)(νmax, cm−1): 1672 (C=O). Anal. Calcd for C20H27N2O8P:
C, 52.86; H, 5.99; N, 6.16. Found: C, 52.80; H, 5.85; N, 6.10%. MS
(m/z, %): 454 (M+, 7). 1H NMR (400 MHz, CDCl3): δ 1.24–1.72 (6H,
m, 3CH2), 1.58 (6H, s, 2CH3), 2.95–2.98 (4H, m, 2CH2), 3.65 (3H, d,
3JPH = 11 Hz, POCH3), 3.74 (3H, d, 3JPH = 11 Hz, POCH3), 4.86 (1H,
d, 2JHP = 28 Hz, CH), 7.70 (2H, d, 3JHH = 7 Hz, 2CH aromatic), 7.99
(2H, d, 3JHH = 7 Hz, 2CH aromatic). 13C NMR (100.6 MHz, CDCl3):
δ 22.48 (CH2), 25.69 (2CH3), 38.23 (d, 1Jcp = 140.8 Hz, P-CH), 44.59
2
(2CH2), 55.07 (2CH2), 52.94 and 54.05 (2d, JCP = 8 Hz, P(OCH3)2),
71.95 (CMe2), 101.93 (d, 2JCP = 36 Hz, C=C), 123.14, 129.82, 130.36,
Scheme 2 Suggested mechanism for formation of
compound 5.
3
and 146.34 (aromatic), 138.25 (=CON), 167.27 (d, JCP = 6.0 Hz,
C=O), 31P NMR (162 MHz, CDCl3): δ 33.25.
Diethyl {(4-nitrophenyl)-(2,2-dimethyl-4-oxo-6-piperidin-1-yl-4H-
[1,3]dioxin-5-yl)methyl}phosphonate (5e): Yield: 87%; Yellow oil.
IR (KBr)(νmax, cm−1): 1670 (C=O). Anal. Calcd for C22H31N2O8P: C,
54.77; H, 6.48; N, 5.81. Found: C, 55.90; H, 6.57; N, 5.80%. MS (m/z,
%): 482 (M+, 5). 1H NMR (400 MHz, CDCl3): δ 1.25 and 1.33 (6H, 2t,
3JHH = 7 Hz, 2CH3), 1.44–1.60 (6H, m, 3CH2), 1.62 (6H, s, 2CH3),
2.93–3.04 (4H, m, 2CH2), 4.07–4.15 (4H, m, 2POCH2), 5.17 (1H,
d, 2JHP = 28 Hz, CH), 7.50 (2H, d, 3JHH = 7 Hz, 2CH aromatic), 8.16
(2H, d, 3JHH = 7 Hz, 2CH aromatic). 13C NMR (100.6 MHz, CDCl3):
δ 16.85 and 17.08 (2CH3), 22.41 (CH2), 25.63 (2CH3), 38.35 (d, 1Jcp =
140.8 Hz, P-CH), 44.46 (2CH2), 55.02 (2CH2), 62.80 and 63.52 (2d,
2Jcp = 7 Hz, 2POCH2), 72.13 (CMe2), 102.24 (d, 2JCP = 36 Hz, C=C),
123.47, 129.94, 130.45, and 146.32 (aromatic), 137.82 (=CON),
167.34 (d, 2JCP = 6.0 Hz, C=O), 31P NMR (162 MHz, CDCl3): δ 33.20.
IR spectra were recorded on a Shimadzu IR-470 spectrometer.1H,
13C and 31P NMR spectra were recorded on Bruker DRX-400 Avance
spectrometer in CDCl3 using TMS as internal standard. The chemicals
used in this work were purchased from Fluka (Buchs, Switzerland)
and were used without further purification. Compound 1 was prepared
as previously described in the literature.10
Synthesis of compounds 5a–e; general procedure
A mixture of trialkyl phosphite (2 mmol) at room temperature over
2 min was added dropwise to a magnetically stirred solution of
Meldrum’s acid (2 mmol) and aryl aldehydes (2 mmol) in dichloro-
methane (15 mL). The reaction mixture was then stirred for 1 minute.
Piperidine (2 mmol) was added and the reaction mixture was stirred
for another 24h at room temperature. The solvent was removed under
reduced pressure and the residue was purified by column chromato-
graphy on silica gel (60, 230–400 mesh) using ethyl acetate–hexane
(3:1) mixture as eluent.
We gratefully acknowledge financial support from the Research
Council of Islamic Azad University of Arak and the Islamic
Azad University of Zahedan, Iran.
Dimethyl {(phenyl)-(2,2-dimethyl-4-oxo-6-piperidin-1-yl-4H-[1,3]-
dioxin-5-yl)methyl}phosphonate (5a): Yield: 88%;Yellow oil. IR (KBr)
(νmax, cm−1): 1675 (C=O). Anal. Calcd for C20H28NO6P: C, 58.67; H,
6.89; N, 3.42. Found: C, 58.55; H, 6.97; N, 3.50%. MS (m/z, %): 409
(M+, 8). 1H NMR (400 MHz, CDCl3): δ 1.59–1.77 (6H, m, 3CH2), 1.67
Received 27 March 2013; accepted 22 April 2013
Paper 1301840 doi: 10.3184/174751913X13701025495780
Published online: 18 July 2013
3
(6H, s, 2CH3), 2.94–2.97 (4H, m, 2CH2), 3.71 (3H, d, JPH = 11 Hz,
POCH3), 3.74 (3H, d, 3JPH = 11 Hz, POCH3), 4.98 (1H, d, 2JHP = 28 Hz,
CH), 7.16–7.53 (5H, m, 5CH aromatic).13C NMR (100.6 MHz,
References
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2
P-CH), 44.09 (2CH2), 52.43 and 53.00 (2d, JCP = 8 Hz, P(OCH3)2),
2
3
4
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53.62 (2CH2), 72.21 (CMe2), 101.27 (d, 2JCP = 36 Hz, C=C), 127.69,
128.92, 129.28, and 130.68 (aromatic), 138.32 (=CON), 166.96 (d,
3JCP = 6.0 Hz, C=O), 31P NMR (162 MHz, CDCl3): δ 33.08.
Diethyl {(phenyl)-(2,2-dimethyl-4-oxo-6-piperidin-1-yl-4H-[1,3]-
dioxin-5-yl)methyl}phosphonate (5b): Yield: 90%; Yellow oil. IR
(KBr) (νmax, cm−1): 1680 (C=O). Anal. Calcd for C22H32NO6P: C,
60.40; H, 7.37; N, 3.20. Found: C, 60.48; H, 7.25; N, 3.26%. MS (m/z,
8
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%): 437 (M+, 3). H NMR (400 MHz, CDCl3): δ 0.91 and 1.18 (6H,
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3.84–3.98 (4H, m, 2CH2), 4.05–4.14 (4H, m, 2POCH2), 5.01(1H,
2
d, JHP = 28 Hz, CH), 7.04–7.43 (5H, m, 5CH aromatic). 13C NMR
(100.6 MHz, CDCl3): δ 17.33 and 17.47 (2CH3), 23.34 (CH2), 26.97
1
(2CH3), 40.29 (d, Jcp = 140.8 Hz, P-CH), 45.37 (2CH2), 62.83 and
63.61 (2d, 2Jcp = 7 Hz, 2POCH2), 54.64 (2CH2), 73.48 (CMe2), 102.56
2
(d, JCP = 36 Hz, C=C), 127.14, 129.02, 130.29, and 130.68
(aromatic), 139.65 (=CON), 168.03 (d, 3JCP = 6.0 Hz, C=O), 31P NMR
(162 MHz, CDCl3): δ 30.84.
Dimethyl {(4-chlorophenyl)-(2,2-dimethyl-4-oxo-6-piperidin-1-yl-
4H-[1,3]dioxin-5-yl)methyl}phosphonate (5c): Yield: 92%; Yellow
oil. IR (KBr)(νmax, cm−1): 1673 (C=O). Anal. Calcd for C20H27ClNO6P:
C, 54.12; H, 6.13; N, 3.16. Found: C, 54.20; H, 6.24; N, 3.04%. MS
1
(m/z, %): 443 (M+, 10). H NMR (400 MHz, CDCl3): δ 1.10–1.73
(6H, m, 3CH2), 1.52 (6H, s, 2CH3), 3.08–3.80 (4H, m, 2CH2), 3.54
(3H, d, 3JPH = 11 Hz, POCH3), 3.76 (3H, d, 3JPH = 11 Hz, POCH3), 4.77

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