Electrophilicity parameters of 5-benzylidene-2,2-dimethyl[1,3]dioxane-4,6- diones (benzylidene meldrum's acids)

Article abstract of DOI:10.1021/jo702590s

(Chemical Equation Presented) Kinetics of the reactions of four benzylidene Meldrum's acids 1 with acceptor-substituted carbanions 2 were studied photometrically in DMSO at 20°C. The reactions follow second-order kinetics, and the second-order rate consta

Full text of DOI:10.1021/jo702590s

Electrophilicity Parameters of
5-Benzylidene-2,2-dimethyl[1,3]dioxane-4,6-diones (Benzylidene
Meldrum’s Acids)
Oliver Kaumanns and Herbert Mayr*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstr. 5-13 (Haus F), 81377 Mu¨nchen, Germany
herbert.mayr@cup.uni-muenchen.de
ReceiVed December 13, 2007
Kinetics of the reactions of four benzylidene Meldrum’s acids 1 with acceptor-substituted carbanions 2
were studied photometrically in DMSO at 20 °C. The reactions follow second-order kinetics, and the
second-order rate constants were found to follow the correlation log k2 (20 °C) ) s(N + E) (eq 1), which
was used to calculate the electrophilicity parameters E for compounds 1. Hammett correlations are given,
which allow one to assign electrophilicity parameters for various â,â-acceptor substituted styrenes and
thus to predict a large number of absolute rate constants for a manifold of Michael additions. The reactions
of primary and secondary amines are approximately 2 orders of magnitude faster than predicted by the
correlation (1), supporting transition states which are stabilized by hydrogen bridges from NH to the
carbonyl groups of the benzylidene Meldrum’s acids.
Introduction
enol ethers,10 and ketene acetals11 amino-substituted diarylcar-
benium ions and structurally related quinone methides have been
used as reference electrophiles. It has been shown that eq 1
also holds for the reactions of ordinary Michael acceptors and
electron-deficient arenes with carbanions12-14 and other strong
nucleophiles.15,16
Numerous kinetic investigations have shown that the rate
constants for the reactions of carbocations with carbanions and
neutral π-nucleophiles can be described by eq 1, wherein s and
N are nucleophile-dependent parameters and E is an electrophile-
dependent parameter:1,2
(6) (a) Brotzel, F.; Mayr, H. Org. Biomol. Chem. 2007, 5, 3814-3820.
(b) Brotzel, F.; Kempf, B.; Singer, T.; Zipse, H.; Mayr, H. Chem. Eur. J.
2007, 13, 336-345.
log k2(20 °C) ) s(N + E)
(1)
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3688.
In order to assign nucleophilicity parameters for strong
nucleophiles, such as carbanions,3-5 amines,6-8 enamines,9 silyl
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9, 2209-2218.
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(b) Burfeindt, J.; Patz, M.; Mu¨ller, M.; Mayr, H. J. Am. Chem. Soc. 1998,
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3396.
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(b) Ofial, A. R.; Mayr, H. Macromol. Symp. 2004, 215, 353-367. (c) Mayr,
H.; Ofial, A. R. In Carbocation Chemistry; Olah, G. A., Prakash, G. K. S.,
Eds.; Wiley: Hoboken, NJ, 2004; pp 331-358. (d) Mayr, H.; Kuhn, O.;
Gotta, M. F.; Patz, M. J. Phys. Org. Chem. 1998, 11, 642-654. (e) Mayr,
H.; Patz, M.; Gotta, M. F.; Ofial, A. R. Pure Appl. Chem. 1998, 70, 1993-
2000. (f) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938-
957.
(2) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-
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10.1021/jo702590s CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/04/2008
2738
J. Org. Chem. 2008, 73, 2738-2745

5-Benzylidene-2,2-dimethyl[1,3]dioxane-4,6-diones
TABLE 1. N and s Parameters of the Carbanions 2a-i in DMSO
The nucleophilic attack at the electron-deficient double bond
of Michael acceptors has long been a field of great interest in
physical organic chemistry. Bernasconi studied the kinetics of
the reactions of numerous amines, carbanions, and alkoxides
toward Michael acceptors, e.g., benzylidene indandiones and
benzylidene Meldrum’s acids in DMSO/H2O mixtures.17-21
Rappoport investigated nucleophilic vinylic substitutions22 on
chloro-substituted benzylidene Meldrum’s acids which follow
the addition-elimination mechanism.21,23 In recent years, Oh
and Lee24 reported mechanistic studies and rate constants of
the reactions of benzylamines with benzylidene Meldrum’s acids
and other Michael acceptors in acetonitrile.
Benzylidene Meldrum’s acids 1 are usually prepared by
condensation of an aldehyde with Meldrum’s acid in the
presence of catalytic amounts of acid25 or base in benzene or
chloroform solutions,26 but in some cases subsequent cycliza-
tions occur.26c Improved yields have been obtained under
solvent-free conditions by grinding the reactants,27 by DMAP
catalysis,28 or by using water29 or ionic liquids30 as solvents.
Compounds 1 are useful reactants for the synthesis of pharma-
cologically active heterocyclic compounds.31
In 1964, benzylidene Meldrum’s acids have been termed
“electronically neutral Lewis acids” by Swoboda and Wessely.25
Schuster, Polansky and Wessely reported equilibrium constants
for the addition of methoxide to a variety of neutral organic
Lewis acids, including benzylidene Meldrum’s acids.32 The
formation of zwitterionic addition products from neutral organic
Lewis acids and amines or phosphanes was reported by
Margaretha.33
a From ref 5. b From ref 4.
SCHEME 1. Reaction of the Carbanions 2 (K+ Salts) with
the Benzylidene Meldrum’s Acids 1a-d
(16) Remennikov, G. Y.; Kempf, B.; Ofial, A. R.; Polborn, K.; Mayr,
H. J. Phys. Org. Chem. 2003, 16, 431-437.
(17) Bernasconi, C. F.; Panda, M. J. Org. Chem. 1987, 52, 3042-3050.
(18) Bernasconi, C. F. Tetrahedron 1989, 45, 4017-4090.
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5329-5336. (b) Bernasconi, C. F.; Leonarduzzi, G. D. J. Am. Chem. Soc.
1980, 102, 1361-1366.
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5251-5257. (b) Bernasconi, C. F.; Leonarduzzi, G. D. J. Am. Chem. Soc.
1982, 104, 5133-5142.
(21) Bernasconi, C. F.; Ketner, R. J.; Chen, X.; Rappoport, Z. J. Am.
Chem. Soc. 1998, 120, 7461-7468.
(22) Rappoport, Z. Acc. Chem. Res. 1992, 25, 474-479.
(23) Ali, M.; Biswas, S.; Rappoport, Z.; Bernasconi, C. F. J. Phys. Org.
Chem. 2006, 19, 647-653.
Rate and equilibrium constants for the additions of amines
to the electrophilic double-bond of these Michael acceptors were
determined34a,b and the kinetics of their hydrolytic cleavage was
investigated in 10% aqueous methanol.34b Regio- and stereo-
selective Cu-catalyzed additions of alkynes35 and R2Zn to
benzylidene Meldrum’s acids have recently been reported by
Carreira36 and Fillion.37
The higher electrophilic reactivity of benzylidene Meldrum’s
acids compared to benzylidene malonic esters, their open-chain
analogues, is related to the unusually high acidity of the
Meldrum’s acid, which was attributed to the fixed bis-anti
conformation of the ester groups.38 Recently, Nakamura em-
(24) (a) Oh, H. K.; Kim, T. S.; Lee, H. W.; Lee, I. Bull. Korean Chem.
Soc. 2003, 24, 193-196. (b) Oh, H. K.; Lee, J. M. Bull. Korean Chem.
Soc. 2002, 23, 1459-1462.
(25) (a) Swoboda, G.; Swoboda, J.; Wessely, F. Monatsh. Chem. 1964,
95, 1283-1304. (b) Review: Kunz, J. F.; Margaretha, P.; Polansky, O. E.
Chimia 1970, 24, 165-208.
(26) (a) Schuster, P.; Polansky, O. E.; Wessely, F. Monatsh. Chem. 1964,
95, 53-58. (b) McNab, H. Chem. Soc. ReV. 1978, 7, 345-358. (c)
Margaretha, P. Tetrahedron Lett. 1970, 11, 1449-1452. (d) Chen, B. C.
Heterocycles 1991, 32, 529-597.
(27) Kaupp, G.; Naimi-Jamal, M. R.; Schmeyers, J. Tetrahedron 2003,
59, 3753-3760.
(28) Narsaiah, A. V.; Basak, A. K.; Visali, B.; Nagaiah, K. Synth.
Commun. 2004, 34, 2893-2901.
(29) Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori,
G. Tetrahedron Lett. 2001, 42, 5203-5205.
(30) Hu, Y.; Wei, P.; Huang, H.; Le, Z.-G.; Chen, Z.-C. Synth. Commun.
2005, 35, 2955-2960.
(34) (a) Schreiber, B.; Martinek, H.; Wolschann, P.; Schuster, P. J. Am.
Chem. Soc. 1979, 101, 4708-4713. (b) Margaretha, P.; Leitlich, J.;
Polansky, O. E. Tetrahedron Lett. 1969, 11, 4429-4432. (c) Margaretha,
P.; Schuster, P.; Polansky, O. E. Tetrahedron 1971, 27, 71-79.
(35) (a) Fujimori, S.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46,
4964-4967. (b) Kno¨pfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M. J.
Am. Chem. Soc. 2005, 127, 9682-9683. (c) Kno¨pfel, T. F.; Carreira, E. M.
J. Am. Chem. Soc. 2003, 125, 6054-6055.
(31) (a) Tu, S.; Zhu, X.; Zhang, J.; Xu, J.; Zhang, Y.; Wang, Q.; Jia, R.;
Jiang, B.; Zhang, J.; Yao, C. Bioorg. Med. Chem. Lett. 2006, 16, 2925-
2928. (b) Pita, B.; Sotelo, E.; Suarez, M.; Ravina, E.; Ochoa, E.; Verdecia,
Y.; Novoa, H.; Blaton, N.; De Ranter, C.; Peeters, O. M. Tetrahedron 2000,
56, 2473-2479.
(32) Schuster, P.; Polansky, O. E.; Wessely, F. Tetrahedron 1966, Suppl.
8 (II), 463-483.
(33) Margaretha, P.; Polansky, O. E. Monatsh. Chem. 1969, 100, 576-
583.
(36) Watanabe, T.; Kno¨pfel, T. F.; Carreira, E. M. Org. Lett. 2003, 5,
4557-4558.
(37) Fillion, E.; Wilsily, A. J. Am. Chem. Soc. 2006, 128, 2774-2775.
J. Org. Chem, Vol. 73, No. 7, 2008 2739

Kaumanns and Mayr
1
TABLE 2. Characterized Michael Adducts and Some Characteristic H NMR Chemical Shiftsa
electrophile
nucleophile
product (yield/%)
δ (Ha)/ppm
δ (Hb)/ppm
δ (Hc)/ppm
Ja,b/Hz
Jb,c/Hz
1a (X ) H)
2h
2b
2b
2d
2e
2g
2h
2b
2b
2d
2g
2h
2a
2b
2b
2d
2d
2g
3ahb,c
5.76c
4.38
4.43-4.47
4.22
1b (X ) OMe)
3bbb
4.89
4.78
5.10
12.4
12.4
12.6
1b
1b
1b
1b
4bb (41)
4bd (48)
4be (66)d
4bg (85)
3bh (64)c,e,f
3cbb
4.43-4.47
3.94
3.6
4.0
4.96
4.06
4.44
5.19
12.0
1b
5.68c
1c (X ) NMe2)
1c
1c
1c
4.33
4.33-4.43
4.28
4.87
4.70
5.75
5.24
12.6
12.0
12.4
12.4
4cb
4.33-4.43
3cd (66)e
3cgb
4.46
1c
3ch (46)c,e,f
3dab,g
5.64c
1d (X ) jul)
3.94/3.88g
4.20
5.71/5.85g
4.80
4.65
5.68
5.12
1d
1d
1d
1d
1d
3dbb
12.6
12.0
12.0
12.5
12.8
4db
4.26-4.30
4.26-4.20
4.12
4.18
4.33
3ddb
4dde
4.01
3.3
3dgb
5.24
a Anionic products 3 were characterized in DMSO-d6; neutral products 4 were characterized in CDCl3; for numbering, see Scheme 1. b Analysis of the
crude reaction mixture. c Enol form of the dimedone moiety. d Diastereomers in a ratio of 58:42. e The given yield refers to the reaction in 1,2-dimethoxyethane.
f Thermally instable, NMR spectra were taken from the crude reaction mixture in DMSO. g Diastereomers in a ratio of 52:48.
ployed the “reactive hybrid orbital (RHO) theory” to rationalize
the high acidity of Meldrum’s acid.39
As part of our program of developing comprehensive nu-
cleophilicity and electrophilicity scales, we have now studied
the kinetics of the reactions of carbanions 2a-i (Table 1) with
the benzylidene Meldrum’s acids 1a-d in DMSO (Scheme 1).
We will show that eq 1 can be used to describe the rates of
these reactions and report on the determination of the electro-
philicity parameters E for the Michael acceptors 1a-d. We will
furthermore present correlations between the E parameters of
these and related electrophiles with Hammett’s substituent
constants σp and thus provide data to predict absolute rate
constants for a manifold of Michael additions.
Results and Discussion
Reaction Products. When equimolar amounts of 1 and 2-K+
were combined in DMSO, the potassium salts 3-K+ were formed
1
and characterized by H and 13C NMR spectroscopy without
further workup (Scheme 1, Table 2). Compounds 4 were
synthesized from equimolar amounts of 1 and 2-K+ in DMSO
FIGURE 1. Correlation of (log k2)/s versus the nucleophilicity
or 1,2-dimethoxyethane solution and subsequent treatment with
hydrochloric acid. Since analogous products can be expected
for different combinations of the electrophiles 1a-d with the
carbanions 2a-i, product studies have not been performed for
all combinations which were studied kinetically. In all cases
quantitative product formation was indicated by the complete
decolorization of the solutions and the fact that the NMR spectra
obtained after mixing 1 and 2-K+ showed the signals of 3-K+
exclusively. The differences in the isolated yields reported in
Table 2 are due to nonoptimized workup procedures.
parameters N of the carbanions 2a-i for the reactions of benzylidene
Meldrum’s acids 1a-d with carbanions 2a-i in DMSO at 20 °C.
3ch do not show the absorption of Hc around δ ) 5 ppm.
Instead, a signal at δ ) 13.5 ppm was observed due to the enol
form of the dimedone fragment.40 As a consequence, Hb absorbs
as a singlet at δ ) 5.7 ppm in the anions 3ah, 3bh, and 3ch.
Kinetic Investigations with Carbanions. The kinetic inves-
tigations were performed at 20 °C in DMSO as a solvent.
Because the benzylidene Meldrum’s acids 1a-d show absorp-
tion bands at 325, 366, 460, and 484 nm, respectively, and
neither the products 3 nor the carbanions 2a-i absorb at these
wavelengths, the progress of the reactions can be monitored
photometrically at the absorption maxima of these electrophiles.
Due to the high rates of these reactions, the stopped-flow
technique was generally employed. All reactions described in
this paper proceed quantitatively. The carbanions were either
Generally, the Michael adducts 3 and 4 show 1H NMR spectra
with resonances Ha, Hb and Hc in the range of δ ) 3.8-5.9
ppm with small coupling constants of 3.3-4.0 Hz between Ha
and Hb, and large coupling constants of approximately 12.5 Hz
between Hb and Hc. Only the dimedone adducts 3ah, 3bh, and
(38) (a) Arnett, E. M.; Harrelson, J. A., Jr. J. Am. Chem. Soc. 1987,
109, 809-812. (b) Wang, X.; Houk, K. N. J. Am. Chem. Soc. 1988, 110,
1870-1872. (c) Wiberg, K. B.; Laidig, K. E. J. Am. Chem. Soc. 1988,
110, 1872-1874.
(39) Nakamura, S.; Hirao, H.; Ohwada, T. J. Org. Chem. 2004, 69,
4309-4316.
(40) (a) Shi, D. Q.; Chen, J.; Zhuang, Q. Y.; Wang, X. S.; Hu, H. W.
Chin. Chem. Lett. 2003, 14, 1242-1245. (b) For analogous NMR spectra
of related compounds, see ref 13.
2740 J. Org. Chem., Vol. 73, No. 7, 2008

5-Benzylidene-2,2-dimethyl[1,3]dioxane-4,6-diones
TABLE 3. Second-Order Rate Constants k2 for the Reactions of
the Carbanions 2a-i (K+ salts) with Electrophiles 1a-d in DMSO
at 20 °C
nitrile anion (2d) react two to four times faster with each of the
electrophiles 1b-d than expected from the correlations, whereas
the nitroethyl anion (2a), the malonate anion (2b), and the
phenyl nitronate (2f) are about two times less reactive than
expected.
electrophile
Ea
nucleophile
k2/M-1 s-1
1a (X ) H)
-9.15b
2h
2i
2.93 × 105
1.16 × 104
1.15 × 106
1.96 × 106
2.51 × 106
7.42 × 105
2.23 × 105
1.89 × 105
6.00 × 104
2.39 × 103
2.89 × 104
4.76 × 104
7.21 × 104
1.27 × 104
3.87 × 103
3.50 × 103
9.82 × 102
2.12 × 104
6.08 × 103
7.98 × 103
1.48 × 104
2.83 × 103
4.93 × 102
3.84 × 102
1.08 × 102
Though the correlations are only of moderate quality, one
can conclude that the relative electrophilicities of benzylidene
Meldrum’s acids 1a-d are almost independent of the nature of
the carbanions. Therefore we have calculated the E parameters
for 1a-d by least-squares minimization of ∆2 ) Σ(log k - s(N
+ E))2 using the second-order rate constants k2 given in Table
3 and the N and s parameters of 2a-i from Table 1. With the E
parameters thus determined a different illustration of the
reactivities of the carbanions 2a-i toward the electrophiles
1a-d and the reference electrophiles 1e-m becomes possible
(Figure 2). The plots of log k2 against the electrophilicity
parameters E show that in general, the reactivities of the
carbanions 2a-i toward 1a-d correlate well with the electro-
philicity parameter E, but the previously mentioned deviations
are, again, evident. While, for the sake of clarity, the poorly
correlating carbanions 2d and 2f are not included in Figure 2,
one can see that the reactivities of 1b-d with the anion of
diethyl malonate (2b) are below the correlation line defined by
the reference electrophiles 1e-m. On the other hand the
dimedone anion (2h) generally reacts faster with electrophiles
1b-d than expected from the rates of its reactions with the
reference electrophiles 1e-m.
1b (X ) OMe)
-10.28
2b
2c
2d
2e
2f
2g
2h
2i
2b
2c
2d
2e
2f
2g
2h
2ac
2b
2c
2d
2e
2f
1c (X ) NMe2)
-12.76
-13.97
1d (X ) jul)
2g
2h
a The E parameters for 1a-d result from a least-squares minimization
of ∆2 ) Σ(log k2 - s(N + E))2 which uses the second-order rate constants
k2 (this table) and the N and s parameters of the carbanions 2a-i given in
Table 1. Details of the calculation of E are discussed below. b A value of
-9.5 is expected if the same set of reference nucleophiles would be
employed as for compounds 1b-d. c The tetra-n-butyl ammonium salt of
2a was used for the kinetic measurements.
The different behavior of the dimedone anion (2h) toward
the Michael acceptors 1a-d and the reference electrophiles
1e-m reminds of the previously reported behavior of 2h toward
electrophiles 5-X,13 6-X,13 and 7-X,14 but the reason for these
deviations is presently not understood.
used as preformed potassium salts, or the corresponding CH
acids were deprotonated with 1.05 equiv of potassium tert-
butoxide before use. UV-vis spectroscopic monitoring of the
titration showed that complete deprotonation of 2f-H was
obtained with 1.05 equiv of KO-t-Bu. In order to confirm that
the slight excess of KO-t-Bu did not affect the observed rate
constants, we have also generated the carbanion 2f by treating
2f-H with 0.27 equiv of KO-t-Bu. In this case, the concentration
of the carbanion 2f is given by the quantity of KO-t-Bu, and
the second-order rate constant was found to be the same as that
obtained with the slight excess of KO-t-Bu (Supporting Infor-
mation, Tables S7a and S7b). In order to obtain pseudo-first-
order kinetics, the carbanions were used in large excess (10-
100 equiv) over the electrophiles. In all cases reported in Table
3, an exponential decay of the concentration of the electrophiles
1a-d was observed (eq 2).
Figure 3 shows that there are clearly two distinct correlation
lines for the different types of electrophiles, one for the reactions
of 2h with the quinone methides 1h-m and the benzhydrylium
ions 1e-g and another one for the structurally related Michael
acceptors 1-X, 5-X, 6-X, and 7-X. Despite this clear separation,
one should note that all deviations from the lower (reference)
line are much less than 1 order of magnitude. One can, therefore,
conclude that the reactivity order of the carbanions 2a-i derived
from the rates of the reactions with the reference electrophiles
1e-m also holds roughly for the Michael acceptors 1a-d and
that the E parameters derived in Table 1 can be employed for
the general prediction of rate constants for the reactions of 1a-d
with nucleophiles.
The positioning of the combination of dimedone 2h with 1a
on the “wrong” correlation line of Figure 3 is due to the fact
that the electrophilicity parameter of 1a has been derived from
the reactions of 1a with 2i and 2h (Figure 1), i.e., two carbanions
which react faster with 1b-c than expected from their N-
parameters. If all carbanions 2a-i had been used for the
determination of E(1a), and 1a followed the same pattern as
shown for compounds 1b-d in Figure 1 one would expect the
slightly smaller electrophilicity parameter E(1a) ≈ -9.5. An
-d[1]/dt ) k1ψ[1]
(2)
The first-order rate constants k1ψ were obtained by least-
squares fitting of the time-dependent absorbances At of the
electrophiles to the exponential function At ) A0 exp(-k1ψt) +
C. Plots of k1ψ versus the carbanion concentration [2] resulted
in linear correlations with almost zero intercepts, the slopes of
which gave the second-order rate constants k2 (Table 3).
Correlation Analysis. If eq 1 holds for the reactions of the
benzylidene Meldrum’s acids 1a-d with carbanions, the plots
of (log k2)/s versus the nucleophilicity parameter N should have
slopes of 1.0. Figure 1 shows that this is approximately the case.
However, small systematic deviations of some of the nucleo-
philes are obvious. The dimedone anion (2h) and the malono-
J. Org. Chem, Vol. 73, No. 7, 2008 2741

Kaumanns and Mayr
FIGURE 2. Rate constants for the reactions of carbanions 2a-i with electrophiles 1a-d (open symbols) and with reference electrophiles 1e-m
(filled symbols) in DMSO (20 °C).
SCHEME 2. Comparison of the Electrophilicity Parameters
E of Benzylidene Meldrum’s Acids 1a-d with Those of
Some Reference Electrophilesa
FIGURE 3. Rate constants for the reaction of the dimedone anion
(2h) with electrophiles 1a-d and 5-7 (open symbols, log k2 ) 0.734E
+ 12.4) and reference electrophiles 1e-m (filled symbols, log k2 )
0.767E + 12.5) in DMSO at 20 °C.
experimental test for this hypothesis was not possible because
the reactions of 1a with 2a-g are too fast to be measured with
conventional stopped-flow instruments.
a E (1a) has been calculated from the rate constants of the reactions of
1a with only two nucleophiles (see text). Depending on the choice of other
reaction partners, the electrophilicity E may be lower by 0.3-0.4 units.
Scheme 2 compares the electrophilicities of the benzylidene
Meldrum’s acids 1a-d with those of some reference electro-
philes and shows that their electrophilic reactivities cover a range
of almost 5 orders of magnitude.
electron-donating substituents in p-position exert comparable
retarding effects.
Substitution of the E parameters for 1d, 6-jul, and 7-jul into
the correlation equations listed in Table 4 yields σp(jul) ) -0.91,
-0.86, and -0.92, respectively. When the average of these
values, σp(jul) ) -0.89, is used to locate 5-jul in Figure 4, a
correlation with a similar slope (F ) 3.5) results for the reactions
of compounds 5-X. A considerably more negative value for σp
(-2.03) of the julolidyl substituent has recently been derived
According to Figure 4, the electrophilicity parameters E of
1a-c, 6-X, 7-X, and 8-X correlate well with Hammett’s σp-
values for H, OMe, and NMe2. The corresponding plots of E
+
versus σp show larger scatter. From the slopes of these
correlations (5.20 - 5.74, Table 4), one can derive reaction
constants of F ≈ 3.8 ( 0.3 for reactions with nucleophiles of s
) 0.7 (Table 1), indicating that in all four reaction series
+
2742 J. Org. Chem., Vol. 73, No. 7, 2008

5-Benzylidene-2,2-dimethyl[1,3]dioxane-4,6-diones
Table 5 furthermore shows that the experimental rate
constants are generally 20-120 times greater than the calculated
values. The reaction of morpholine with 1c in DMSO is even
580 times faster than calculated (entry 29). Though deviations
from experimental values by two orders of magnitude are still
within the confidence limit of eq 1,2,42 the constantly higher
experimental rate constants for the additions of secondary
amines to 1a-d may be indicative of a change of mechanism.
Schuster,34 Bernasconi,20,44 and Oh24 presented evidence that
the transition states of amine additions to 1 are stabilized by
hydrogen bridging from NH to the carbonyl group (six-
membered transition state TS6) or from NH to the carbanionic
center (four-membered ring TS4). Analogous hydrogen bridging
may account for the finding that glycinamide and semicarbazide
react 200 times faster with 1a than predicted by eq 1 (Table 5,
entries 33, 34).
FIGURE 4. Correlation between the electrophilicity parameters E of
electrophiles 1a-d (open symbols) and 5-8 (closed symbols) in DMSO
with Hammett’s σp-values (from ref 41). σp for “jul” calculated as
described in the text.
TABLE 4. Correlation between Electrophilicity Parameters E for
Various Series of Electrophiles and Hammett’s Substituent
Constants σp
electrophile
correlation, E )
R2
6-X
1a-c
8-X
5.71σ - 8.83
5.37σ - 9.08
5.74σ - 9.34
5.20σ - 10.0
1.00
0.99
0.99
0.99
This type of transition state stabilization by hydrogen bridging
is not possible in additions of carbanions to 1a-d, the rates of
which have been used to derive the E parameters of these
electrophiles (Table 3). A related study has recently shown that
additions of secondary amines to benzylidene indandiones 7-X
are only three times faster than predicted by eq 1.14 It has,
therefore, been concluded that H-bridging as indicated in TS6
and TS4 cannot have a large effect on the transition states of
the additions of secondary amines to 7-X.
7-X
from the electrophilicities of benzhydrylium ions.42 From the
similar slopes of the correlation lines for the different series of
electrophiles in Figure 4 one can derive the general validity of
the electrophilicity order 5-X > 6-X ≈ 1-X > 8-X > 7-X.
Reactions with Other Nucleophiles. In order to check the
applicability of the electrophilicity parameters E of benzylidene
Meldrum’s acids 1a-d (Scheme 2) for predicting the rates of
reactions with other types of nucleophiles, we compared
predicted and experimental rate constants for the addition
reactions of amines to the electrophilic double bonds of 1a-d.
Kinetics of the reactions of piperidine and morpholine with
compounds 1b-d have been determined in DMSO, using the
same methodology as described above for the reactions with
carbanions. The second-order rate constants for the reactions
with piperidine in DMSO (Table 5, entries 8, 13, 18) were found
to be 3-6 times greater than those in DMSO/H2O (50/50) which
have previously been determined by Bernasconi (entries 10,
15)17 and confirmed by us (entries 9, 14). The reactions are
roughly 1 order of magnitude faster in neat DMSO than in water
(cf entries 8/11 and 13/16). Solvent effects of similar magnitude
have been observed for the corresponding additions of mor-
pholine (Table 5, entries 20-32). Though variations of the
solvent can be expected to affect nucleophilicities as well as
electrophilicities, in the derivation of the parameters for eq 1
solvent effects were exclusively considered in the nucleophile
specific parameters N and s.4 Though this procedure was
reported to cause some problems for the reactions with 7-X,14
differential solvent effects on the electrophilicities of 1a-d have
not been considered.
Conclusion
Benzylidene Meldrum’s acids are another group of electro-
philes, the reactivities of which can be described by correlation
eq 1. While the reactivities with carbanions can be reproduced
with an accuracy of better than a factor of 5, primary and
secondary amines react approximately 102 times faster than
predicted by eq 1. In line with previous work, these deviations
are explained by additional stabilizing effect in the transition
states (hydrogen bridging).
Accordingly, calculated and experimental rate constants for
the reactions of 1 with tertiary amines, which cannot be
accelerated by hydrogen bridging, differ by only 1 order of
magnitude.45 It is, therefore, concluded that the E parameters
for 1a-d in this work can be used to characterize the
electrophilic potential of the title compounds.
Experimental Section
Benzylidene Meldrum’s Acids 1a-c. Benzylidene Meldrum’s
acids 1a-c were prepared by following a procedure for the synthesis
of structurally related benzylidene barbituric acids:46 Equimolar
amounts of para-substituted benzaldehyde and Meldrum’s acid were
stirred in EtOH under reflux for 2 h. The product precipitates
immediately after cooling the reaction mixture to room temperature.
(41) Exner, O. Correlation Analysis of Chemical Data; Plenum: New
York, 1988.
(42) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker,
B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J.
Am. Chem. Soc. 2001, 123, 9500-9512.
(43) For a comprehensive database of reactivity parameters E, N, and s:
www.cup.lmu.de/oc/mayr/DBintro.html.
(44) Bernasconi, C. F.; Kanavarioti, A. J. Am. Chem. Soc. 1986, 108,
7744-7751.
(45) Baidya, M.; Mayr, H. Chem. Commun. 2008, DOI: 10.1039/
b801811a.
(46) Xu, Y.; Dolbier, W. R., Jr. Tetrahedron 1998, 54, 6319-6328.
J. Org. Chem, Vol. 73, No. 7, 2008 2743

Kaumanns and Mayr
TABLE 5. Comparison of Calculated and Experimental Second-Order Rate Constants for the Addition of Amines to Benzylidene Meldrum’s
Acids 1a-d in Different Solvents (20 °C)
k2/L mol-1 s-1
entry
nucleophile
piperidine
N/s (solvent)
electrophile
calcda
experimental (solvent)
1
2
3
4
5
6
7
8
9
17.19/0.71 (DMSO)
1a
5.11 × 105 b
2.09 × 106 (DMSO/H2O ) 90/10)c
1.40 × 106 (DMSO/H2O ) 70/30)c
6.69 × 105 (DMSO/H2O ) 50/50)c
1.70 × 105 (H2O)c
18.13/0.44 (H2O)
8.94 × 103
8.06 × 104
2.70 × 105 (H2O, 25 °C)c
2.30 × 106 (CH3CN, 25 °C)d
1.20 × 106 (CHCl3, 25 °C)d
1.93 × 106 (DMSO)e
17.19/0.71 (DMSO)
1b
1c
2.89 × 105 (DMSO/H2O ) 50/50)e
2.67 × 105 (DMSO/H2O ) 50/50)c
1.70 × 105 (H2O, 25 °C)c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
18.13/0.44 (H2O)
2.84 × 103
1.40 × 103
9.50 × 105 (CH3CN, 25 °C)d
1.71 × 105 (DMSO)e
17.19/0.71 (DMSO)
3.76 × 104 (DMSO/H2O ) 50/50)e
3.96 × 104 (DMSO/H2O ) 50/50)c
2.10 × 104 (H2O, 25 °C)c
18.13/0.44 (H2O)
2.31 × 102
1.93 × 102
(1.71 × 105)b
1.10 × 105 (CH3CN, 25 °C)d
1.80 × 104 (DMSO)e
17.19/0.71 (DMSO)
16.96/0.67 (DMSO)
1d
1a
6.23 × 103 (DMSO/H2O ) 50/50)e
8.88 × 105 (DMSO/H2O ) 90/10)c
7.33 × 105 (DMSO/H2O ) 70/30)c
3.19 × 105 (DMSO/H2O ) 50/50)c
1.47 × 105 (H2O)c
morpholine
15.62/0.54 (H2O)
3.12 × 103
1.75 × 105 (H2O, 25 °C)c
4.0 × 105 (CH3CN, 25 °C)d
1.0 × 105 (CHCl3, 25 °C)d
1.56 × 105 (DMSO/H2O ) 50/50)c
9.90 × 104 (H2O, 25 °C)c
16.96/0.67 (DMSO)
15.62/0.54 (H2O)
16.96/0.67 (DMSO)
1b
1c
(2.99 × 104)b
6.64 × 102
6.51 × 102
3.78 × 105 (DMSO)e,f
1.11 × 104 (DMSO/H2O ) 50/50)e
1.46 × 104 (DMSO/H2O ) 50/50)c
1.00 × 104 (H2O, 25 °C)c
15.62/0.54 (H2O)
12.29/0.58 (H2O)g
11.05/0.52 (H2O)i
3.50 × 101
6.63 × 101
9.73
glycinamide
semicarbazide
1a
1a
1.34 × 104 (H2O)h
1.64 × 103 (H2O)h
a Calculated according to eq 1 by using the E parameters for 1a-d from Table 3 and the N and s parameters for amines from refs 7, 8, and 43. b For neat
DMSO. c From ref 17. d From ref 34. e This work. f Fast kinetics, complete decay of the monitored absorbance within 6 ms. g From ref 7. h From ref 18.
i From ref 8.
After filtration and recrystallization from EtOH, the electrophiles
1a-c were obtained as colored crystals. 1H and 13C NMR spectra
for 1a-c agreed with those described in the literature.26,47 UV-
vis spectra of 1a-d in DMSO are shown in Figure S1 of the
Supporting Information.
5-[2-Acetyl-1-(4-methoxyphenyl)-3-oxobutyl]-2,2-dimethyl-
1,3-dioxane-4,6-dione (4bg). A mixture of 1b (365 mg, 1.39 mmol)
and 2g-K+ (202 mg, 1.46 mmol) in dry DMSO (2 mL) was stirred
until the color of the solution disappeared. Then the reaction mixture
was poured on cold water (5 mL) and acidified with 2 M aq HCl.
The precipitate was filtered and dissolved in CH2Cl2. After removal
of the traces of water by filtering the solution over a hot cotton
batting, the solvent was evaporated and the residue was dried in
vacuum. 4bg (400 mg, 85%). Colorless solid. Mp: 116.6-
2,2-Dimethyl-5-(julolidin-9-ylmethylene)-1,3-dioxane-4,6-di-
one (1d). Meldrum’s acid (716 mg, 4.97 mmol) and 9-formyl-
julolidine (1.00 g, 4.97 mmol) were added to EtOH (25 mL). The
solution turned purple immediately. After 10 min under reflux, the
solution was allowed to cool to room temperature. The product
precipitated from the solution, was filtered and recrystallized from
EtOH. The product 1d (900 mg, 2.75 mmol, 55%) was obtained
as purple crystals. Mp: 138.0-138.4 °C. Further attempts to
optimize the yield have not been made. 1H NMR (300 MHz,
CDCl3): δ ) 1.73 (s, 6 H, C(CH3)2), 1.96 (quint, J ) 5.7 Hz, 4 H,
2 × CH2), 2.74 (t, J ) 5.7 Hz, 4 H, 2 × CH2), 3.36 (t, J ) 5.7 Hz,
4 H, 2 × CH2), 7.85 (s, 2 H, ArH), 8.15 (s, 1 H). 13C NMR (75.5
MHz, CDCl3): δ ) 21.0 (t, CH2), 27.2 (q, CH3), 27.5 (t, CH2),
50.4 (t, CH2), 102.6 (s), 103.0 (s), 119.4 (s), 120.5 (s), 136.6 (d,
Car), 149.3 (s), 157.5 (d, dC-H), 161.8 (s), 165.6 (s). Signal
assignments are based on additional gHSQC experiments. MS (ESI,
positive): m/z (%) ) 328 (7) [M + H]+, 270 (100). Anal. Calcd
for C19H21NO4 (327.38): N, 4.28; C, 69.71; H, 6.47. Found: N,
4.27; C, 69.45; H, 6.36.
1
116.9 °C. H NMR (300 MHz, CDCl3): δ ) 1.27, 1.62 (2 s, 2 ×
3 H, C(CH3)2), 1.95 (s, 3 H, COCH3), 2.32 (s, COCH3), 3.74 (s, 3
3
3
H, OMe), 4.06 (d, J ) 4.0 Hz, 1 H, Ha), 4.44 (dd, J ) 4.0 Hz,
12.0 Hz, 1 H, Hb), 5.19 (d, 3J ) 12 Hz, 1 H, Hc), 6.79 (d, 3J ) 9.0
Hz, 2 H, ArH), 7.19 (d, J ) 9.0 Hz, 2 H, ArH). 13C NMR (75.5
3
MHz, CDCl3): δ ) 28.3 (q, C(CH3)2), 28.5 (q, C(CH3)2), 29.9 (q,
COCH3), 30.6 (q, COCH3), 43.2 (d, Cb), 48.2 (d, Ca), 55.4 (q,
OCH3), 71.0 (d, Cc), 105.8 (s, C(CH3)2), 114.7 (d, Ar), 128.5 (s),
130.8 (d, Ar), 159.7 (s), 165.0 (s, CO2), 165.9 (s, CO2), 202.4 (s,
COCH3), 203.5 (s, COCH3). Signal assignments are based on
additional DEPT and gHSQC experiments. ESI-MS (negative): m/z
(%) ) 361 (100) [M - H+]-. HR-MS: calcd 362.1366 (C19H22O7),
found 362.1327.
Reaction of 4-Dimethylaminobenzylidene Meldrum’s Acid
(1c) with Potassium Dicyanomethanide (2d-K+). A mixture of
1c (71.5 mg, 0.260 mmol) and 2d-K+ (27.1 mg, 0.260 mol) was
stirred in DME (2 mL) at room temperature. After decolorization
of the solution, stirring was continued for 5 min. A yellow solid
precipitated, and hexane was added to support the precipitation.
(47) (a) Schuster, I.; Schuster, P. Tetrahedron 1969, 25, 199-208. (b)
Cornelis, A.; Lambert, S.; Laszlo, P.; Schaus, P. J. Org. Chem. 1981, 46,
2130-2134. (c) Fillion, E.; Dumas, A. M.; Hogg, S. A. J. Org. Chem.
2006, 71, 9899-9902.
2744 J. Org. Chem., Vol. 73, No. 7, 2008

5-Benzylidene-2,2-dimethyl[1,3]dioxane-4,6-diones
The precipitate was washed with diethyl ether/hexane. 3cd (65 mg,
Rate constants k1ψ (s-1) were obtained by fitting the single
exponential At ) A0 exp(-k1ψt) + C to the observed time-dependent
electrophile absorbance (the monitored wavelenghts are given in
the Supporting Information). As depicted in the Supporting
Information, the second-order rate constants k2 (Table 3) were
obtained from the slopes of the linear plots of k1ψ versus the
carbanion concentrations [2].
1
66%). Yellow solid. Mp: 129.1-129.5 °C. H NMR (400 MHz,
DMSO-d6): δ ) 1.46 (s, 6 H, C(CH3)2), 2.85 (s, 6 H, NMe2), 4.28
3
3
(d, J ) 12.4 Hz, 1 H, Hb), 5.75 (d, J ) 12.0 Hz, 1 H, Hc), 6.61
(d, 3J ) 8.8 Hz, 2 H, ArH), 7.29 ppm (d, 3J ) 8.8 Hz, 2 H, ArH).
13C NMR (100.5 MHz, DMSO-d6): δ ) 25.7 (q, C(CH3)2), 26.6
(d, Cc), 40.1 (q, NMe2), 43.2 (d, Cb), 73.2 (s, Ca), 99.7 (s, C(CH3)2),
111.8 (d, Ar), 115.1 (s, CN), 128.4 (d, Ar), 129.8 (s), 149.2 (s),
164.6 ppm (s, CO2). Signal assignments are based on additional
gHSQC experiments. ESI-MS (negative): m/z (%) ) 340 (100)
[M - K+]-, 300 (63), 212 (23).
Acknowledgment. Financial support by the Deutsche For-
schungsgemeinschaft (Ma 673-17/4) and the Fonds der Che-
mischen Industrie is gratefully acknowledged. We thank Dr.
Armin Ofial for helpful discussions.
Kinetics. For the kinetic experiments, standard stopped-flow
UV-vis-spectrophotometer systems were used in their single
mixing mode. Solutions of the electrophiles 1 in DMSO were mixed
with solutions of the carbanions 2 in DMSO (either generated by
deprotonation of 2-H with 1.05 equiv of KO-t-Bu in DMSO or by
dissolving 2-K+ in DMSO). In order to obtain pseudo-first-order
kinetics, the carbanions were used in large excess (10-100 equiv)
over the electrophiles. The temperature of the solutions was kept
constant (20 ( 0.1 °C) by using circulating bath thermostats.
Supporting Information Available: Details of the kinetic
experiments, synthetic procedures, and NMR spectra of all char-
acterized compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO702590S
J. Org. Chem, Vol. 73, No. 7, 2008 2745