Phospha-Michael Addition to in Situ Prepared 5-Arylmethylidene Meldrum's Acids

Article abstract of DOI:10.1055/s-0033-1341085

Knoevenagel condensation reaction of an aldehyde and Meldrum's acid produces a 5-arylmethylidene Meldrum's acid, which undergoes Michael addition of a trialkyl phosphite under solvent-free conditions to afford the title compounds in good yields.

Full text of DOI:10.1055/s-0033-1341085

LETTER
▌1331
letter
Phospha-Michael Addition to In Situ Prepared 5-Arylmethylidene Meldrum’s
Acids
Preparation of 5-Arylmethylidene Meldrum’s Acids
Mehdi Adib,*a Ehsan Sheikhi,a Narjes Rezaei,a Hamid Reza Bijanzadeh,b Peiman Mirzaeic
a
School of Chemistry, University College of Science, University of Tehran, P. O. Box 14155-6455 Tehran, Iran
Fax +98(21)66495291; E-mail: madib@khayam.ut.ac.ir
b
Department of Chemistry, Tarbiat Modares University, P. O. Box 14115-175, Tehran, Iran
c
Department of Chemistry, Shahid Beheshti University, Tehran, Iran
Received: 28.02.2014; Accepted after revision: 12.03.2014
knowledge, there are only two reports for the preparation
Abstract: Knoevenagel condensation reaction of an aldehyde and
of β-phosphono malonates by Enders et al. in which reac-
Meldrum’s acid produces a 5-arylmethylidene Meldrum’s acid,
tion of phosphorus nucleophiles and α,β-unsaturated mal-
which undergoes Michael addition of a trialkyl phosphite under sol-
vent-free conditions to afford the title compounds in good yields.
onates under catalytic conditions has led to interesting
products.15
Key words: trialkyl phosphites, aldehydes, Meldrum’s acid, 2-[(di-
alkoxyphosphoryl)arylmethyl]malonates, phospha-Michael addi-
tion
Due to the unique properties of P-containing organic com-
pounds, the development of synthetic methods which
enable facile access to these useful entities are desirable.
As part of our current studies on the development of effi-
cient and facile methods for the preparation of biological-
ly active organic compounds from readily available
building blocks,16 herein we report a novel reaction lead-
ing to β-phosphono malonates and α-hydroxy phospho-
nates.
Phosphonates have received considerable attention be-
cause of their chemical and biological importance.1 These
compounds act as enzyme inhibitors in a variety of pro-
cesses because of their structural analogy that refer to the
hydrolytic stability of the P–C bond.2 Derivatives contain-
ing the phosphonate system have been shown to possess a
broad range of useful pharmacological activities, and are
used as herbicides,3 antibiotics,4 antiviral agents,5 anti-
HIV agents,6 and blood pressure regulators.7
Thus, a mixture of Meldrum’s acid (1), a benzaldehyde 2,
and a trialkyl phosphite 3 was stirred at ambient tempera-
ture under solvent-free conditions. The progress of the re-
action was monitored by TLC. The reaction went to
completion within eight hours to afford the corresponding
During recent years there has been considerable investiga-
tion on α-hydroxy phosphonates and the corresponding α-
hydroxy phosphonic acids. In particular, α-hydroxy phos-
phonates have been shown to possess a wide range of bi-
ological activities.8 Many of these compounds have
exhibited antibacterial, antivirus, antibiotic, pesticidal and
antitumor activities.9,10 Furthermore, many α-functional-
ized phosphonates, such as α-amino,11 α-acetoxy,12 α-halo,13
and α-keto phosphonates14 are prepared from α-hydroxy
phosphonates.
dialkyl
2-[(dialkoxyphosphoryl)arylmethyl]malonates
4a–i and dialkyl hydroxy(aryl)methylphosphonates 5a–i.
1H NMR analysis of the reaction mixtures clearly indicat-
ed formation of compounds 4 and 5 in good yields. The re-
sults are summarized in Scheme 1 and Table 1.17
All dialkyl hydroxy(aryl)methylphosphonates 5a–i are
known compounds and were characterized by comparison
of their physical and spectral data with those of authentic
samples reported in the literature.18–21
This broad range of applications has made the develop-
ment of new and efficient phosphonate syntheses very
valuable. Consequently, a variety of phosphonate synthe-
ses have been reported in the literature. To the best of our
The structures of dialkyl 2-[(dialkoxyphosphoryl)aryl-
methyl]malonates 4 were deduced on the basis of IR, 1H
NMR, 13C NMR and 31P NMR spectroscopy, mass spec-
trometry and elemental analysis. The IR spectrum of 4a
O
O
OH
R
R
O
R
solvent-free
r.t., 8 h
O
O
O
O
O
Ar
P
+
2 ArCHO
+
2 P(OR)3
+
O
O
2
3
O
O
Ar
P
R
5
1
O
O
R
R
4
Scheme 1 Reaction between Meldrum’s acid, benzaldehydes and trialkyl phosphites
SYNLETT 2014, 25, 1331–1334
Advanced online publication: 08.05.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1341085; Art ID: ST-2014-D0175-L
© Georg Thieme Verlag Stuttgart · New York

1332
M. Adib et al.
LETTER
PCHCH moiety. Two characteristic resonances were ob-
served at δ = 166.9 (as a doublet, JPC = 21.2 Hz) and
Table 1 Synthesis of β-Phosphono Malonates 4 and α-Hydroxy-
phosphonates 5
3
167.6 for the two carbonyls of the malonate moiety as
well as three CHs and a quaternary carbon with appropri-
ate chemical shifts and multiplicities for the phenyl sub-
Entry Ar
R
Yield (%) Mp (°C)
of 4a
of 4
Yield (%)
of 5a
1
stituent. The H decoupled 31P NMR spectrum of 4a
1
Me 4a, 4515b 80–81
5a, 4118
showed a signal at δ = 26.67 in agreement with the pro-
posed structure.17
As shown in Scheme 2, there are three possible conforma-
tional diastereomers for β-phosphono malonates 4, as a re-
sult of rotational barrier around C–C single bond. On the
basis of the J values in the 1H NMR and 13C NMR spectra,
the approximate weight of the individual rotamers in the
CH3O
2
3
4
Me 4b, 43
Me 4c, 4215b 103–104
94–95
5b, 4219
5c, 4019
5d, 3919
CH3
Cl
1
equilibrium can be determined. For example in the H
Me 4d, 47
Me 4e, 42
95–96
NMR spectral data of 4a, the observed vicinal coupling
constant for the two H atoms is 3JHH = 11.8 Hz, which is
in close proximity to that of two vicinal H atoms with an
anti relationship, and is far from the expected J value for
the other two rotamers with a gauche relation of these two
vicinal H atoms, i.e. the equilibrium is shifted in favor of
rotamer 4a-I. This conclusion is confirmed by the 13C
NMR data of 4a. One of the two carbonyl C atoms is
gauche to the P atom with no observed coupling, while the
other is in a 180° torsional angle (anti relationship) with
3JPC = 21.2 Hz (Figure 1).
5
102–103
5e, 4320
Cl
6
7
8
9
Et 4f, 46
Et 4g, 41
Et 4h, 44
Et 4i, 43
colorless liquid 5f, 4018
colorless liquid 5g, 4521
colorless liquid 5h, 4621
colorless liquid 5i, 4321
Cl
H3C
F
gauche relation of P
and C atoms: no coupling
anti relation of two H atoms:
3JHH = 11.8 Hz
H
CO2Me
MeO2C
Ph
a Isolated yields.
PO(OMe)2
H
showed absorptions at 1735 and 1014 cm–1 indicative for
C=O and P–O bonds, respectively. The mass spectrum of
4a displayed the molecular ion [M+] peak at m/z = 330,
which was 32 mass units (a MeOH) more than that of the
1:1:1 adduct of Meldrum’s acid, benzaldehyde and tri-
methyl phosphite with the loss of an acetone molecule.
anti relation of P and C atoms:
3JPC = 21.2 Hz
Figure 1 J values in the favored rotamer of 4a
Although no detailed mechanistic studies have been car-
ried out, a possible explanation for the reaction is pro-
posed in Scheme 3. First Meldrum’s acid (1) may
condense with the aldehyde 2 to give 5-arylmethylidene
Meldrum’s acid intermediate 6. Conjugate addition of the
phosphite 3 on 6, may lead to formation of the ketene
phosphonium carboxylate intermediate 7 by removal of
an acetone molecule. Next, the alkyl group of the phos-
phonium moiety may be attacked by the adjacent carbox-
ylate group to afford the ketene phosphonate intermediate
8. On the other hand, nucleophilic attack of another trial-
kyl phosphite 3 on the aldehyde 2, may lead to formation
of the phosphonium alkoxide intermediate 9, which may
be protonated by the H2O generated from the condensa-
tion of Meldrum’s acid and the aldehyde, to give α-hy-
1
The H NMR spectrum of 4a showed two singlets (δ =
3.38 and 3.78) arising from the two ester methoxy groups.
3
Two doublets were observed (δ = 3.44 and 3.64; JPH
=
10.7, 10.9 Hz, respectively) for the two diastereotopic
POCH3 groups. Two doublets of doublet were seen [δ =
3.97 (2JPH = 20.4 Hz, 3JHH = 11.8 Hz) and δ = 4.20 (3JPH
=
3
10.2 Hz, JHH = 11.8 Hz)] for the PCHCH moiety, along
with characteristic signals with appropriate chemical
shifts for the five aromatic protons. The 1H decoupled 13C
NMR spectrum of 4a showed characteristic signals at δ =
1
43.7 (as a doublet, JPC = 139.2 Hz, due to P–CH), 52.6
and 53.0 (due to the two CO2CH3 groups), 52.9 and 53.8
(as two doublets, 2JPC = 7.0, 6.5 Hz, respectively, arising
from the two diastereotopic POCH3 groups), and 53.1 for
H
H
H
CO2Me
CO2Me
MeO2C
Ph
H
H
MeO2C
Ph
Ph
PO(OMe)2
PO(OMe)2
PO(OMe)2
CO2Me
H
CO2Me
4a-I
4a-II
4a-III
Scheme 2 Three possible conformational diastereomers of 4a
Synlett 2014, 25, 1331–1334
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of 5-Arylmethylidene Meldrum’s Acids
1333
2,2-dimethyl-1,3-
dioxane-4,6-dione
O
O
O
O
O
O
R
O
O
O
.
.
R
X
R
R
X
O
O–
O
P(OR)3 (3)
O
O
O
O
ROH
O
O
O
O
R
P+
P
P
+
O
– Me2CO
O
O
R
O
O
O
O
O
X
R
R
R
R
X
1
2
X
4
6
7
8
O–
H
O
OH
O
O
R
–OH
R
R
R
P+
P
P+
H2O
O
O
P(OR)3
+
O
O
R
O
R
O
O
O
3
R
R
X
X
X
X
2
9
10
5
Scheme 3 Possible mechanism for the formation of dialkyl 2-[(dialkoxyphosphoryl)arylmethyl]malonates 4 and dialkyl hydroxy(aryl)meth-
ylphosphonates 5
MeO2C
Ph
CO2Me
MeOH (3 equiv)
r.t., 8 h
O
O
PhCHO
+
P(OMe)3
+
O
O
PO(OMe)2
4a
Scheme 4 Reaction between Meldrum’s acid, benzaldehyde and trimethyl phosphite in the presence of MeOH
Systems; Hildebrand, R. L., Ed.; CRC Press: Boca Raton,
1983.
droxy phosphonium hydroxide 10. Then nucleophilic
attack of hydroxide ion on the alkyl group of the phospho-
nium moiety may lead to formation of the α-hydroxy
phosphonates 5 by removal of an alcohol molecule. Final-
ly, this alcohol molecule may attack on the ketene group
of phosphonate 8 to afford β-phosphono malonates 4.
(2) (a) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J.
M. J. Med. Chem. 1989, 32, 1652. (b) Smith, W. W.;
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B. J. Phytochemistry 1982, 21, 855. (c) Diddens, H.; Zähner,
H.; Kraas, E.; Göhring, W.; Jung, W. G. Eur. J. Biochem.
1976, 66, 11.
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Patchett, A.; Arison, B. H.; Ormond, R. E.; Kuehl, F. A.;
Albers-Schonberg, G.; Jardetzky, O. Science 1969, 166, 123.
(b) Glamowski, E. J.; Gal, G.; Purick, R.; Davidson, A. J.;
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C.; Castaldi, G. J. Org. Chem. 1989, 54, 1470. (d) Allen, J.
G.; Atherton, F. R.; Hall, M. J.; Hassal, C. H.; Holmes, S.
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(London) 1978, 272, 56.
(5) (a) Van Herrewege, Y.; Penne, L.; Vereecken, C.; Fransen,
K.; Van Der Groen, G.; Kestens, L.; Balzarini, J.; Vanham,
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H.-P.; Qiu, Y.-L.; Ksebati, M. B.; Kern, E. R.; Zemlicka, J.
Tetrahedron 2002, 58, 6047. (c) Aquaro, S.; Calio, R.;
Balzarini, J.; Bellocchi, M. C.; Garaci, E.; Perno, C. F.
Antiviral Res. 2002, 55, 209.
When the reaction was carried out by the use of equimolar
ratios of Meldrum’s acid, benzaldehyde and trimethyl
1
phosphite in the presence of MeOH (3 equiv), H NMR
analysis of the reaction mixture clearly indicated forma-
tion of 4a (Scheme 4). Our attempts to detect the other
product 5a were not successful.
In conclusion, we have developed a one-pot reaction be-
tween Meldrum’s acid, aldehydes and trialkyl phosphites
for the preparation of β-phosphono malonates and α-hy-
droxy phosphonates which are of potential synthetic inter-
est. Solvent-free and mild conditions, ambient
temperature and good yields of the products are the main
advantages of this reaction. The reactions were performed
under neutral conditions, and the starting materials and re-
agents have been mixed without any activation or modifi-
cation.
(6) (a) Alonso, E.; Solis, A.; del Pozo, C. Synlett 2000, 698.
(b) Camp, N. P.; Hawkins, P. C. D.; Hitchcock, P. B.; Gani,
D. Bioorg. Med. Chem. Lett. 1992, 2, 1047.
Acknowledgement
(7) Kido, Y.; Hamakado, T.; Anno, M.; Miyagawa, E.; Motoki,
Y. J. Antibiot. 1984, 37, 965.
(8) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron
Lett. 1990, 31, 5591.
This research was supported by the Research Council of University
of Tehran as a research project (6102036/1/03).
(9) (a) Snoeck, R.; Holy, A.; Dewolf-Peeters, C.; Van Den
Oord, J.; De Clercq, E.; Andrei, G. Antimicrob. Agents
Chemother. 2002, 46, 3356. (b) Hammerschmidt, F. Angew.
Chem., Int. Ed. Engl. 1994, 33, 341. (c) Jennings, L. J.;
Macchia, M.; Parkin, A. J. Chem. Soc., Perkin Trans. 1
References and Notes
(1) (a) Horiguchi, M. Biochim. Biophys. Acta 1972, 261, 102.
(b) Hildebrand, R. L. The Role of Phosphonates in Living
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1331–1334

1334
M. Adib et al.
LETTER
1992, 2197. (d) Sikorski, J. A.; Miller, M. J.; Braccoli, D. S.;
Cleary, D. J.; Corey, S. D.; Font, K. J.; Gruys, K. J.; Han, C.
Y.; Lin, K.-C.; Pansegrau, P. D.; Ream, J. E.; Shnur, D.;
Shah, A.; Walker, M. C. Phosphorus, Sulfur 1993, 76, 115.
= 10.2 Hz, 1 H, PCHCH), 7.21–7.34 (m, 5 H, 5 × CH). 13
NMR (125.8 MHz, CDCl3): δ = 43.7 (d, 1JPC = 139.2 Hz,
C
PCH), 52.6 (CO2Me), 52.9 (d, 2JPC = 7.0 Hz, POMe), 53.0
(CO2Me), 53.1 (PCHCH), 53.8 (d, 2JPC = 6.5 Hz, POMe),
127.9, 128.6 (2 × CH), 129.6 (d, 3JPC = 5.9 Hz, CH), 133.2
(d, 2JPC = 7.0 Hz, C), 166.9 (d, 3JPC = 21.2 Hz, C=O), 167.6
(C=O). 31P NMR (202.5 MHz, CDCl3): δ = 26.67 (P=O). MS
(EI): m/z (%) = 330 (40) [M+], 299 (13), 271 (91), 266 (34),
239 (100), 211 (16), 189 (36), 177 (6), 161 (16), 149 (22),
131 (55), 121 (70), 109 (25), 103 (36), 93 (16), 77 (20), 59
(11). Anal. Calcd for C14H19O7P (330.27): C, 50.91; H, 5.80.
Found: C, 50.7; H, 5.9.
(10) Peters, M. L.; Leonard, M.; Licata, A. A. Cleve. Clin. J. Med.
2001, 68, 945.
(11) Kaboudin, B. Tetrahedron Lett. 2003, 44, 1051.
(12) Firouzabadi, H.; Iranpoor, N.; Sobhani, S.; Amoozgar, Z.
Synthesis 2004, 1771.
(13) Eymery, F.; Lorga, B.; Savignac, P. Tetrahedron 1999, 55,
2671.
(14) Nesterov, V. V.; Kolodiazhnyi, O. I. Tetrahedron 2007, 63,
6720.
Diethyl 2-[(Diethoxyphosphoryl)(4-fluorophenyl)-
methyl]malonate (4i): yield: 0.174 g (43%); colorless
liquid. IR (KBr): 1740, 1735 (C=O), 1604, 1510, 1447,
1369, 1300, 1226, 1161, 1099, 1019 (PO), 962, 849, 794 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 0.93 (t, J = 7.1 Hz, 3 H,
CH2CH3), 1.12 (t, J = 7.0 Hz, 3 H, CH2CH3), 1.22, 1.30 (2 ×
t, J = 7.1 Hz, 6 H, 2 × CH2CH3), 3.75–4.05 (m, 7 H, 3 ×
CH2CH3, PCHCH), 4.13 (dd, 3JHH = 11.3 Hz, 3JPH = 11.1 Hz,
1 H, PCHCH), 4.16 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 6.98
(dd, 3JHH = 8.0 Hz, 3JFH = 8.5 Hz, 2 H, 2 × CH), 7.30–7.36
(m, 2 H, 2 × CH). 13C NMR (128.5 MHz, CDCl3): δ = 13.6,
14.0 (2 × CO2CH2CH3), 16.2 (d, 3JPC = 5.8 Hz, POCH2CH3),
16.3 (d, 3JPC = 6.2 Hz, POCH2CH3), 43.1 (d, 1JPC = 140.0 Hz,
PCH), 53.5 (PCHCH), 61.7, 62.0 (2 × CO2CH2CH3), 62.4 (d,
2JPC = 6.9 Hz, POCH2), 63.1 (d, 2JPC = 6.7 Hz, POCH2),
115.3 (d, 2JFC = 21.3 Hz, CH), 129.5 (dd, 2JPC = 7.1 Hz, 4JFC
= 2.7 Hz, C), 131.5 (dd, 3JFC = 7.7 Hz, 3JPC = 6.3 Hz, CH),
162.3 (d, 1JFC = 250.3 Hz, CF), 166.5 (d, 3JPC = 20.0 Hz,
C=O), 167.1 (C=O). 31P NMR (202.5 MHz, CDCl3): δ =
24.25 (P=O). MS (EI): m/z (%) = 404 (38) [M+], 359 (20),
339 (11), 331 (100), 312 (28), 293 (16), 285 (91), 265 (28),
257 (43), 247 (16), 229 (67), 219 (43), 201 (13), 191 (15),
179 (34), 149 (94), 121 (32), 109 (31), 101 (21), 91 (9), 83
(38), 65 (8), 55 (13). Anal. Calcd for C18H26FO7P (404.37):
C, 53.47; H, 6.48. Found: C, 53.5; H, 6.3.
(15) (a) Enders, D.; Tedeschi, L. Org. Lett. 2001, 3, 3515.
(b) Enders, D.; Tedeschi, L.; Förster, D. Synthesis 2006,
1447.
(16) (a) Adib, M.; Sheikhi, E.; Bijanzadeh, H. R.; Zhu, L. G.
Tetrahedron 2012, 68, 3377. (b) Adib, M.; Sheikhi, E.;
Bagheri, M.; Bijanzadeh, H. R.; Amanlou, M. Tetrahedron
2012, 68, 3237. (c) Adib, M.; Sheikhi, E.; Rezaei, N.
Tetrahedron Lett. 2011, 52, 3191. (d) Adib, M.; Ansari, S.;
Bijanzadeh, H. R. Synlett 2011, 619. (e) Adib, M.;
Karimzadeh, M.; Mahdavi, M.; Sheikhi, E.; Mirzaei, P.
Synlett 2011, 834. (f) Adib, M.; Sheikhi, E.; Kavoosi, A.;
Bijanzadeh, H. R. Tetrahedron 2010, 66, 9263. (g) Adib,
M.; Mohamadi, A.; Sheikhi, E.; Ansari, S.; Bijanzadeh, H.
R. Synlett 2010, 1606. (h) Adib, M.; Sheikhi, E.; Kavoosi,
A.; Bijanzadeh, H. R. Synthesis 2010, 4082.
(17) General Procedure for the Preparation of Compounds 4
and 5, Exemplified on 4a and 5a: A mixture of
benzaldehyde (2 mmol), Meldrum’s acid (1 mmol), and
trimethyl phosphite (2 mmol) was stirred at ambient
temperature for 8 h. Progress of the reaction was monitored
by TLC. After completion of the reaction, the products were
purified by column chromatography using n-hexane–EtOAc
(2:1) as eluent. The solvent was removed and the products
were obtained.
Dimethyl 2-[(Dimethoxyphosphoryl)phenylmethyl]-
malonate (4a): yield: 0.149 g (45%); white powder; mp 80–
81 °C. IR (KBr): 1735 (C=O), 1498, 1440, 1312, 1244,
1212, 1161, 1046, 1014 (PO), 916, 856, 829, 728 cm–1. 1H
NMR (500.1 MHz, CDCl3): δ = 3.38 (s, 3 H, CO2CH3), 3.44
(d, 3JPH = 10.7 Hz, 3 H, POCH3), 3.64 (d, 3JPH = 10.9 Hz, 3
H, POCH3), 3.78 (s, 3 H, CO2CH3), 3.97 (dd, 3JHH = 11.8 Hz,
2JPH = 20.4 Hz, 1 H, PCHCH), 4.20 (dd, 3JHH = 11.8 Hz, 3JPH
(18) Texier-Boullet, F.; Foucaud, A. Synthesis 1982, 165.
(19) Seven, O.; Polat-Cakir, S.; Hossain, M. S.; Emrullahoglu,
M.; Demir, A. S. Tetrahedron 2011, 67, 3464.
(20) Yang, F.; Zhao, D.; Lan, J.; Xi, P.; Yang, L.; Xiang, S.; You,
J. Angew. Chem. Int. Ed. 2008, 47, 5646.
(21) Wu, Q.; Zhou, J.; Yao, Z.; Xu, F.; Shen, Q. J. Org. Chem.
2010, 75, 7498.
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