A new source of methylene Meldrum's acid. Reactions with enamines

Article abstract of DOI:10.1081/SCC-120004851

The unsymmetrical Knoevenagel-Michael product derived from Meldrum's acid, phenyl Meldrum's acid and formaldehyde was prepared as a pure, stable and crystalline product. This compound readily dissociates under the reaction conditions to produce methylene

Full text of DOI:10.1081/SCC-120004851

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A NEW SOURCE OF METHYLENE MELDRUM'S ACID.
REACTIONS WITH ENAMINES
Francis X. Smith a , Brian D. Williams a & Edward C. Evans a
a Department of Chemistry , King's College , Wilkes-Barre, PA, 18711, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Francis X. Smith , Brian D. Williams & Edward C. Evans (2002) A NEW SOURCE OF METHYLENE MELDRUM'S
ACID. REACTIONS WITH ENAMINES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:13, 2009-2015, DOI: 10.1081/SCC-120004851
To link to this article: http://dx.doi.org/10.1081/SCC-120004851
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SYNTHETIC COMMUNICATIONS, 32(13), 2009–2015 (2002)
A NEW SOURCE OF METHYLENE
MELDRUM’S ACID. REACTIONS
WITH ENAMINES
*
Francis X. Smith, Brian D. Williams,
and Edward C. Evans
Department of Chemistry, King’s College,
Wilkes-Barre, PA 18711, USA
ABSTRACT
The unsymmetrical Knoevenagel–Michael product derived
from Meldrum’s acid, phenyl Meldrum’s acid and formalde-
hyde was prepared as a pure, stable and crystalline product.
This compound readily dissociates under the reaction condi-
tions to produce methylene Meldrum’s acid. This
Knoevenagel–Michael product was used to explore a new
application of methylene Meldrum’s acid: the reaction with
enamines.
Methylene Meldrum’s acid (isopropylidene methylenemalonate or
2,2-dimethyl-5-methylene-1,3-dioxane-4,6-dione) (I) is a reactive dienophile
and Michael acceptor with a fleeting existence.[1] Early methods for the
generation of this intermediate involve oxidation reactions of
5-seleno derivatives.[2] Several years ago we described a method of
*Corresponding author. Fax: 570-825-9049; E-mail: fxsmith@kings.edu
2009
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

2010
SMITH, WILLIAMS, AND EVANS
generation that used either a mixture of formaldehyde and Meldrum’s acid
or a mixture of the Knoevenagel–Michael adduct (II) of Meldrum’s acid
and formaldehyde with additional formaldehyde.[3] More recently a
novel betaine (III) prepared from pyridine, formaldehyde, and
Meldrum’s acid was reported by Zia-Ebrahimi and Huffman and
shown to form methylene Meldrum’s acid under certain conditions.[4]
These workers demonstrated that this compound could be used to
form products in high yield with dienes, indole and active methylene
compounds (Scheme 1).
Scheme 1.
We wish to report a new convenient source of methylene Meldrum’s
acid (I). This source is the stable crystalline Knoevenagel–Michael bis
adduct (IV) derived from Meldrum’s acid, phenyl Meldrum’s acid and for-
maldehyde. This compound appears to readily generate methylene
Meldrum’s acid (I) in the presence of enamines and reacts with the enamines
forming phenyl Meldrum’s acid (V) as a byproduct (Scheme 2).
Scheme 2.

METHYLENE MELDRUM’S ACID
2011
This present work is the result of an attempt to find a source of
methylene Meldrum’s acid that could be used to test its reactivity with
enamines. The idea that enamines would be reactive with methylene
Meldrum’s acid is suggested by the previously reported reaction[4,5] with
indole which can be considered a cyclic aromatic enamine. The enamines
attack the electron deficient double bond of the Meldrum’s acid derivative
and this results in 3-oxoalkylmalonate derivatives after aqueous workup.
The following five 3-oxoalkylmalonate derivatives have been formed in
good yield (Scheme 3).
Scheme 3.
For such reactions with ordinary enamines it would be presumably
necessary to generate methylene Meldrum’s acid (I) under anhydrous condi-
tions and in non-hydroxylic solvents. Examination of the reactivity of the
unsymmetrical bis-adduct (IV) showed it to be markedly more reactive than
the symmetrical adduct (II). We also found product (III) of Zia-Ebrahimi
and Huffman to be quite reactive toward these enamines under similar con-
ditions. Compounds VI through VIII were formed with comparable yields
by this method. Also it might be noted, that as far as we know, there are no
prior reports of other unsymmetrical Knoevenagel–Michael bis-adducts
derived from Meldrum’s acid and a mono substituted Meldrum’s acid.

2012
SMITH, WILLIAMS, AND EVANS
EXPERIMENTAL
Meldrum’s Acid, phenyl Meldrum’s acid, 37% formaldehyde and
piperidine were obtained from commercial sources and used without
purification in the preparation of diisopropylidene 1-phenyl-1,1,3,3-
propanetetracarboxylate. Enamines 1-piperidino-1-cyclopentene, 1-mor-
pholino-1-cyclohexene and 1-morpholino-1-cycloheptene were also
obtained from commercial sources and used without purification in the
reactions with Meldrum’s acid while the aza cyclic enamine was synthesized
in benzene and reacted in situ with Meldrum’s acid. Melting points were
determined in a capillary tube on a Thomas Hoover MP apparatus. IR
1
spectra were recorded on a Mattson Instruments Polaris Spectrometer. H
and 13C NMR spectra were recorded in CDCl3 on a Varian EM360L CW
60 MHz spectrometer upgraded with an Anasazi Instruments, Inc.
EFT FT NMR upgrade with Carbon-13 accessory. Carbon type assignments
were made from 13C NMR DEPT data. Quantitative Technologies Inc.
Whitehouse, NJ and Atlanta Microlab, Inc. Norcross, GA performed
analyses.
Diisopropylidene
1-Phenyl-1,1,3,3-Propanetetracarboxylate
(IV):
Meldrum’s Acid, 14.4 g (100 mmol) and phenyl Meldrum’s acid, 22.0 g
(100 mmol) were stirred in 200 mL of absolute ethanol and 9.0 mL of 37%
formaldehyde (100 mmol) was added followed by twenty drops of piperi-
dine. After stirring for two days, the crystalline product was removed by
filtration and washed with additional ethanol. The white crystalline product
melted at 165ꢀC with vigorous gas evolution. 70% Yield. 1H NMR
(60 MHz, CDCl3) d 8.01 (br s, 5H), 4.84 (t, 1H), 3.59 (d, 2H), 2.38 (br s,
9H), 1.80 (s, 3H). 13C NMR (60 MHz, CDCl3) d 164.99 (4 C¼O), 134.69 (C),
129.39 (2 CH), 129.83 (CH), 125.67 (2CH), 106.38 (C), 105.61 (C), 56.85 (C),
41.34 (CH), 36.38 (CH2), 29.70 (CH3), 29.26 (CH3), 27.84 (CH3), 27.60
(CH3). IR (Nujol) 1725, 1760 cmꢁ1 (C¼O). Anal. Calcd for C19H20O8:
C, 60.63; H, 5.32. Found: C, 60.56; H, 5.33.
GeneralProcedure for the Reaction of Methyelne Medlrum’s acid (I)
with Enamines: The bis-adduct (IV), 10 nmol, was stirred in 5.0 mL of THF
resulting in a white slurry. Ten millimoles of the enamine were then added
with continued stirring. A clear yellow solution formed rapidly and after
fifteen minutes the mixture solidified to a nearly white paste. The paste was
dissolved in 40 mL of 0.25 M aqueous HCl solution. The phenyl Meldrum’s
acid byproduct (V), which separated as a white precipitate, was removed by
filtration. The aqueous filtrate was extracted with four 15 mL portions of
methylene chloride. The extracts were combined, dried over magnesium
sulfate and filtered. The methylene chloride was removed by rotary evapora-
tion yielding the white solid products. Alternatively, similar yields were

METHYLENE MELDRUM’S ACID
2013
obtained by chilling the initial aqueous filtrate for twelve hours followed by
collection of the product crystals by filtration.
Isopropylidene 2-Oxocyclopentylmethylmalonate (VI) from 1-Piperidino-
1-cyclopentene: Colorless crystals. 78% yield m.p. 138ꢀC dec. (heptane).
1H NMR (60 MHz, CDCl3) d 4.53 (dd, 1H), 2.18 (om, 9H), 2.02 (s, 3H),
1.90 (s, 3H). 13C NMR (60 MHz, CDCl3) d 220.36 (1 C¼O), 164.75 (1
C¼O), 164.47 (1 C¼O), 104.62 (C), 44.24 (CH), 43.40 (CH), 38.53 (CH2),
30.64 (CH2), 28.56 (CH3), 26.31 (CH2), 26.26 (CH3), 20.56 (CH2). IR
(Nujol) 1770, 1745 cmꢁ1 (C¼O). Anal. Calcd for C12H16O5: C, 59.99; H,
6.71. Found: C, 59.96; H, 6.71.
Isopropylidene 2-Oxocyclohexylmethylmalonate (VII) from 1-Morpholino-
1-cyclohexene: Colorless crystals. 82% yield m.p. 120ꢀC dec. (heptane).
1H NMR (60 MHz, CDCl3) d 3.79 (dd, 1H), 2.21 (om, 11H), 1.57 (s, 3H),
1.51 (s, 3H). 13C NMR (60 MHz, CDCl3) d 212.54 (1 C¼O), 165.29 (1 C¼O),
164.54 (1 C¼O), 104.77 (C), 47.24 (CH), 44.53 (CH), 42.56 (CH2), 35.37
(CH2), 29.14 (CH3), 28.33 (CH2), 27.69 (CH2), 26.73 (CH3), 25.56 (CH2). IR
(Nujol) 1780, 1750, 1700 cmꢁ1 (C¼O). Anal. Calcd for C13H18O5: C, 61.41;
H, 7.13. Found: C, 61.47; H, 7.10.
Isopropylidene 2-Oxocycloheptylmethylmalonate (VIII) from 1-morpho-
lino-1-cycloheptene: Colorless crystals. 76% yield m.p. (heptane). 94ꢀC dec.
(heptane). 1H NMR (60 MHz, CDCl3) d 3.84 (dd, 1H), 2.10 (om, 13H), 1.52
(s, 3H), 1.47 (s, 3H). 13C NMR (60 MHz, CDCl3) d 215.05 (1 C¼O), 164.68
(1 C¼O), 164.23 (1 C¼O), 104.40 (C), 48.52 (CH), 43.98 (CH), 42.78 (CH2),
31.94 (CH2), 29.67 (CH2), 28.95 (CH2), 28.62 (CH3), 28.34 (CH2), 26.45
(CH3), 24.45 (CH2). IR (Nujol) 1790, 1750, 1700 cmꢁ1 (C¼O). Anal.
Calcd for C14H20O5: C, 62.67; H, 7.51. Found: C, 62.82; H, 7.55.
General Procedure for the Reaction of Methylene Meldrum’s Acid with
Aza Cyclic Enamines to form 3-Oxoalkylmalonates (IX) and (X): The
N-carboxy-4-(N-morpholino)-1,2,5,6-tetrahydropyridine enamines were
formed by combining 10 mmol of the N-Carboxy-4-piperidones with
10 mmol of morpholine and a catalytic amount of tosic acid in 80 mL of
benzene. The solutions were refluxed with a Dean-Stark trap for twelve
hours. Upon cooling to room temperature, 10 mmol of diisopropylidene 1-
phenyl-1,1,3,3-propanetetracarboxylate (IV) was added. After 60 min, 40 mL
of 0.25 M HCl was added and the mixtures were vacuum filtered using a
Buchner funnel. The benzene layer was isolated from the aqueous layer
using a separatory funnel. The benzene solution was dried over magnesium
sulfate and the benzene removed by rotary evaporation to yield the white
solid product.
Isopropylidene 3-(N-Ethoxycarbonyl-3-oxo-piperidinyl)methylmalonate
(IX) Derived from N-Carbethoxy-4-(N-morpholino)-1,2,5,6-Tetrahydropyri-
dine: Colorless crystals. 80% yield m.p. 119ꢀC dec. 1H NMR (60 MHz,

2014
SMITH, WILLIAMS, AND EVANS
CDCl3) d 3.81 (om, 3H), 2.50 (om, 9H), 1.49 (s, 3H), 1.46 (s, 3H) 0.80 (t, 3H).
13C NMR (60 MHz, CDCl3) d 208.68 (1 C¼O), 164.92 (1 C¼O), 164.41 (1
C¼O), 154.51 (C¼O), 104.95 (C), 62.12 (CH2), 48.55 (CH2), 46.61 (CH),
44.18 (CH), 43.70 (CH2), 41.02 (CH2), 28.99 (CH3), 26.65 (CH3), 24.61
(CH2), 15.22 (CH3). IR (Nujol) 1800, 1750, 1680 cmꢁ1 (C¼O). Anal.
Calcd for C15H21NO7: C, 55.04; H, 6.47; N 4.28. Found: C, 54.96; H,
6.48; N, 4.22.
Isopropylidene 3-(N-t-butoxycarbonyl-3-Oxo-piperidinyl)methylmalo-
nate (IX) Derived from N-t-Butoxycarbonyl-4-(N-morpholino)-1,2,5,6-tetra-
hydropyridine: Colorless crystals. 75% yield m.p. 132ꢀC dec. 1H NMR
(60 MHz, CDCl3) d 4.39 (om, 2H), 3.96 (om, 2H), 3.27 (om, 2H), 2.89
(om, 4H), 2.09 (s, 3H), 2.00 (s, 3H), 1.73 (s, 9H). 13C NMR (60 MHz,
CDCl3) d 209.86 (1 C¼O), 165.40 (1 C¼O), 164.92 (1 C¼O), 154.07
(C¼O), 104.86 (C), 80.13 (C), 46.11 (CH), 43.57 (CH), 43.11 (CH2), 40.77
(CH2), 40.41 (CH2), 28.80 (CH3), 28.00 (3CH3), 25.89 (CH3), 23.89 (CH2).
IR (Nujol) 1787, 1750, 1710, 1682 cmꢁ1 (C¼O). Anal. Calcd for
C17H25NO7: C, 57.45; H, 7.09; N 3.95. Found: C, 57.49; H, 7.04; N, 3.90.
Reaction of PyridiniummethylMedl rum’s acid (III) with Enamines: The
Pyridiniummethyl Meldrum’s acid (10 mmoles) was stirred in 5 mL of THF.
Ten millimoles of the enamine were added followed by 2 drops of methyl-
sulfonic acid. The mixture was stirred at room temperature for 3 h. The
reaction mixture was then diluted with water, made slightly acidic
with hydrochloric acid, and the crystalline product removed by filtration.
Products VI through VIII were formed with comparable yields to
enamine reactions with Diisopropylidene 1-phenyl-1,1,3,3-propanetetracar-
boxylate (IV).
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Received in the USA July 24, 2001