Reactions of α-isobutyl-α-(methylthio)methylene Meldrum's acid with primary amines in aqueous DMSO

Article abstract of DOI:10.1139/V06-166

The aminolysis of α-isobutyl-α-(methylthio)methylene Meldrum's acid 7 with primary amines, namely, n-butylamine, glycinamide, and methoxyethylamine in DMSO-H₂O (50:50, v/v) at 20°C is overall second-order but first-order in both 7 and amines. The reaction with aminoacetonitrile (AA) is overall third-order, first-order in substrate, and second-order in amine at low amine concentration, while at high amine concentration and high pH the dependence on amine is first-order. A general three-step mechanism has been proposed for all these reactions. For the former group of amines, the first step is a rate-limiting attack of the amine to form the tetrahedral intermediate (T_A^±), followed by a fast acid-base equilibrium and a fast RNH₃⁺- or H ₂O-assisted leaving group expulsion. For AA, general base catalysis was confirmed from the dependence of k_A on [AA]_f and on [OH^-]. For all four amines, a good Bronsted plot of log k ₁ vs. pK_a^AH in DMSO-H₂O (50:50, v/v) with β_nuc = 0.34 ± 0.02 was observed. These observations are consistent with the suggested mechanism.

Full text of DOI:10.1139/V06-166

1
679
Reactions of ␣-isobutyl-␣-(methylthio)methylene
Meldrum’s acid with primary amines in aqueous
DMSO
Supriya Biswas, Mahammad Ali, Zvi Rappoport, and Hatim Salim
Abstract: The aminolysis of α-isobutyl-α-(methylthio)methylene Meldrum’s acid 7 with primary amines, namely, n-
butylamine, glycinamide, and methoxyethylamine in DMSO–H O (50:50, v/v) at 20 °C is overall second-order but first-
2
order in both 7 and amines. The reaction with aminoacetonitrile (AA) is overall third-order, first-order in substrate, and
second-order in amine at low amine concentration, while at high amine concentration and high pH the dependence on
amine is first-order. A general three-step mechanism has been proposed for all these reactions. For the former group of
±
amines, the first step is a rate-limiting attack of the amine to form the tetrahedral intermediate (TA ), followed by a
+
fast acid–base equilibrium and a fast RNH - or H O-assisted leaving group expulsion. For AA, general base catalysis
3
2
–
was confirmed from the dependence of kA on [AA] and on [OH ]. For all four amines, a good Brønsted plot of log k
vs. pKa in DMSO–H O (50:50, v/v) with β = 0.34 ± 0.02 was observed. These observations are consistent with
f
1
AH
2
nuc
the suggested mechanism.
Key words: nucleophilic vinylic substitution reactions, primary amines, α-isobutyl-α-(methylthio)methylene Meldrum’s
acid, three-step mechanism.
Résumé : L’aminolyse du dérivé α-isobutyl-α-(méthylthio)méthylène de l’acide de Meldrum (7) avec des amines pri-
maires telles la butylamine, le glycinamide et la méthoxyéthylamine, dans des solutions contenant 50% de DMSO et
5
0% d’eau, à 20 °C, est une réaction globalement du deuxième ordre, du premier ordre en composés 7 et du premier
ordre en amines. À faible concentration d’amine, la réaction avec l’aminoacétonitrile (AA) est globalement du troi-
sième ordre, soit du premier ordre en substrat et du deuxième ordre en amine; à des concentrations plus élevées
d’amine et à des pH plus élevés, la dépendance sur l’amine est toutefois du premier ordre. D’une façon générale, on
suggère que la réaction se produit par un mécanisme en trois étapes. Pour le premier groupe d’amines, la première
étape est une attaque cinétiquement limitante de l’amine qui conduit à la formation de l’intermédiaire tétraédrique
±
+
(
TA ) et qui est suivie par un équilibre acide-base rapide et une expulsion rapide du groupe partant assistée par RNH3
ou H O. Dans le cas de l’aminoacétonitrile, on a confirmé l’existence d’une catalyse basique générale à partir de la dé-
2
–
pendance de kA sur les [AA] et [OH ]. Pour les quatre amines, dans des solutions contenant 50% de DMSO et 50%
d’eau, on a observé une bonne corrélation de Brønsted entre log k et pKa avec βnuc = 0,34 ± 0,02. Ces résultats
sont en accord avec le mécanisme suggéré.
f
AH
1
Mots clés : réactions de substitution vinylique nucléophile, amines primaires, dérivé α-isobutyl-α-(méthylthio)méthylène
de l’acide de Meldrum, mécanisme en trois étapes.
[
Traduit par la Rédaction] Biswas et al. 1685
Introduction
(1h), reactions with most anionic nucleophiles proceed by a
two-step mechanism (1).
The mechanism of the addition–elimination variant of
nucleophilic vinylic substitution (S V) reactions of electro-
philic alkenes (1), where X and Y are the activating substitu-
ents (1), with anionic nucleophiles (Nu ) may occur either in
The reactions with amine nucleophiles go through a two-
step route with the involvement of acid–base equilibrium as
an additional step, as depicted in Scheme 2 (2).
In the reactions of 6-SMe-Z (Chart 1) with a series of sec-
ondary amines (2), it was shown that general-acid-catalyzed
N
–
a single-step (concerted type) process via a transition state
–
–
AH
H2O
–
(
2) or in a two-step process via an intermediate (3, T ),
MeS departure (k , k3 ) from TA is rate-limiting for
Nu
3
–
which expels the leaving group (LG ) to form the product 4
Scheme 1). Whereas the concerted route is relatively rare
piperidine, while with piperazine, 1-(2-hydroxyethyl-
piperazine), and morpholine deprotonation of TA to TA– is
±
(
Received 29 June 2006. Accepted 10 October 2006. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on
January 2007.
6
1
S. Biswas and M. Ali. Department of Chemistry, Jadavpur University, Kolkata 700 032, India.
Z. Rappoport and H. Salim. Department of Organic Chemistry, the Hebrew University of Jerusalem, Jerusalem 91904, Israel.
1Corresponding author (e-mail: mali@chemistry.jdvu.ac.in).
Can. J. Chem. 84: 1679–1685 (2006)
doi:10.1139/V06-166
© 2006 NRC Canada

1
680
Can. J. Chem. Vol. 84, 2006
Chart 1.
Z
H C
3
O
Ph
LG
Ph
O
CH CH2
MeS
O
O
CH3
O
O
CH3
CH3
C
C
H C
3
C
C
C
C
NO2
CH3
MeS
O
O
9-OMe (LG = MeO)
9
-SMe (LG = SMe )
6-SMe-Z
7
O
SCH3
Z
MeO
Ph
H
O
O
CH3
CH3
(CO) Cr=C
5
C C
R
C
+
NHRR'
–
NO2
O
1
2 for R = Me
10
11-H
13 for R = Ph
Scheme 1.
how the overall reactivity changes in the reactions with a se-
ries of primary amines.
#
Nu
X
Y
R
X
Concerted
route
R
C
C
C
C
Y
Nu
4
Results and discussion
LG
X
Y
2
R
k
1
C
+
Nu
–
k
2
General features
C
k
-1
LG
LG
1
R
X
All reactions were conducted in DMSO–H O (50:50, v/v)
2
–
3
-
at 20 °C, at an ionic strength of 0.5 mol dm maintained
with KCl. Pseudo-first-order conditions were applied
throughout, with the substrate being the minor component.
Rates were measured for the reactions of 7 with n-
butylamine, glycinamide, methoxyethylamine, and amino-
acetonitrile. The representative Fig. 1 shows time-resolved
spectra of the reaction with aminoacetonitrile. The presence
of an isosbestic point indicates a clean reaction. As observed
in the literature, the formation of amine-substituted product
8 produces a blue shift in the UV–vis spectrum (2), and the
spectrum of the reaction mixture at infinite time is identical
with that of the synthetically prepared 8. This was further
Two-step
route
LG
C
C
Y
Nu
3
, TNu–
Scheme 2.
R
C
X
-
R
C
LG
X
+
Y
k
1
LG
C
C
R'R''NH
k
-1
+
Y
HNR'R''
±
T
A
1
1
supported by H NMR and HR-MS studies.
Based on the observations from the reaction of aliphatic
primary (4) and alicyclic secondary amines with 6-SMe-Z
(2), we adopt Scheme 3 for the reactions of primary
R
LG C
NR'R''
R
X
Y
X
k
3
±
K
+ LG
a
C
C
-
C
R''R'N
aliphatic amines (RNH ) with 7.
H+
2
Y
As the intermediate does not accumulate to a detectable
±
level, a steady-state approximation to TA leads us to derive
–
5
3
, TNu
an expression for the second-order rate constant, k , as given
A
by eq. [1].
A
OH


rate-limiting. This conclusion is based on the k OH/k3A ratios
k3
k3
−
3
k 
[RNH ] +
[OH ]
1

2

of 18:36, indicating the independence of k values on the
 k
k−1

1
−1
AH
[1]
k =
A
amine pKa
for the former, while for the latter, the ratio was
A
OH


k3
k3
−
1
79, higher than the observed limit of 5:25 (2, 3) manifesting


[OH ]

1
+
[RNH ] +
2

OH
A
AH
the dependence of k3 /k3 ratio on pKa of the amines.
In the present paper, we examine how the change from a
substituted phenyl group in 6-SMe-Z (Z = H) to the isobutyl
group in 7 (see Chart 1) affects the rate-limiting step(s) and
 k−1
k−1

±
The rate constants corresponding to the conversion of TA
via TA and then to product 8 are shown in eq. [2].
–
©
2006 NRC Canada

Biswas et al.
1681
H C
3
O
A
OH
–
AH
3
+
2
H O
3
CH CH2
k
2
[RNH
2
]+ k
2
[OH ]
k
[RNH ] + k
O
O
CH3
CH3
3
±
H C
3
T
A
–
A
C
+ MeSH
T
C
[
2]
AH
H
2
O
k-2 [RNH3+
RNH
]
+ k-2
O
8
Three cases may arise:
(
[
i) When the acid-catalyzed conversion of T – to TA± is much faster than its reversal, eq. [3] applies.
A
AH
H O
A
OH
[OH− ]
2
3]
k−2 [RNH3
+
] + k−2
>> k [RNH ] + k
2
2
2
The interconversion of T – and T ± can be treated as a rapid pre-equilibrium followed by a rate-limiting MeS departure
–
A
A
AH
(
eq. [4]) and eqs. [5] and [6] hold, where Ka is the acidity constant and K is the ionic product of the solvent (pK = 15.89
w
w
–
3
in DMSO–H O (50:50, v/v) at 20 °C, µ = 0.50 mol dm KCl) (5).
2
CH3 CH3
AH
3
3+
k [RNH ]
CH
CH
C
H C
±
3
O
K
O
a
CH CH2
C
CH
±
O
3
O
O
CH3
[
4]
T
A
H C
3
MeS
C
C
+ MeSH
+
H
O CH
CH
3
3
RNH
RNH
O
O
2
H O
k3
8
T
A
A
AH
AH
[
[
5]
6]
k3 = k3 Ka± / ka
OH
H O
±
2
k3
= k3 K /K
a w
(
[
ii) When the inequality in eq. [7] holds, TA± deprotonation is the rate-limiting step for the conversion
AH
H O
AH
H O
2
2
7]
k−2 [RNH3
+
] + k−2
<< k3 [RNH3 ] + k3
+
of TA± to 8, and eq. [8] and relationships [9] and [10] then hold.
H C
3
O
CH CH2
RNH
k2A [RNH
] +k2OH[OH–]
O
O
CH3
2
Fast
H C
3
[
8]
9]
C
C
+ MeSH
T
A
±
–
–
A
T
CH3
AH
+
H2O
k–2 [RNH ]
k
2
+
O
3
A
A
[
[
(
k3 = k2
OH
OH
10] k3
= k2
iii) The nucleophilic attack becomes the rate-limiting step either via a concerted route or through the formation of TA±
Scheme 2) with subsequent faster steps. For reactions with amines, it is generally accepted that the nucleophilic vinylic
(
±
substitution (S V) occurs through the formation of T (2, 6–7), and eqs. [11] and [12] hold (at high pH, this condition is
N
A
easily met).
A
OH


k3
k3
−
[
[
11]


[RNH ] +
[OH ] >> 1
2

k−1
k−1


12] kA = k1
Reactions of n-BuNH , MeOCH CH NH , and NH COCH NH
2
2
2
2
2
2
2
For the reactions of these three primary amines, a strict second-order kinetics (eq. [12] with k = k ) was observed under all
A
1
+
conditions. All the plots of kobs vs. [RNH ] at pH ~ pK of the amines, where [RNH ]:[RNH ] is 1:1, are linear with negligi-
2 f
a
2
3
–
H2O
OH
ble or no intercept on the rate axis (Fig. 2). A contribution from H O or OH -catalyzed hydrolysis (k
excluded by the small values of the independently determined k
, k1 ) of 7 was
2
1
OH
3
–1 –1
H2O
= 3.27 ± 0.01 dm mol s and k1
= (5.52 ± 0.03) ×
1
–
6
3
–1 –1
1
0
dm mol s .
©
2006 NRC Canada

1
682
Can. J. Chem. Vol. 84, 2006
Fig. 1. Time resolved spectra generated from a kinetic trace for
the reaction between 7 and H NCH CN in DMSO–H O (50:50,
Fig. 2. Plot of kobs vs. [RNH ] for the reaction of 7 with pri-
2 f
mary amines in DMSO–H O (50:50, v/v) at 20 °C.
2
2
2
2
–
3
v/v) with [H NCH CN] = 0.02 mol dm at pH 5.30 and 20 °C.
2
2
0
0
0
0
0
.8
.6
.4
.2
.0
250
300
350
400
Wavelength (nm)
Fig. 3. Plot of kobs vs. [H NCH CN] for the reaction of 7 with
2
2
f
Scheme 3.
aminoacetonitrile in DMSO–H O (50:50, v/v) at 20 °C.
2
H
3
C
CH
3
CH
3
CH
O
3
H C
CH
O
CH
CH
CH
2
O
O
3
H
2
C
O
CH3
k
1
MeS
C
C
C
+ RNH
2
k
-1
3
CH
3
+
O
MeS
O
RNH
2
O
±
7
T
A
CH
CH
3
k
3
A[RNH2]
O
C
3
H C
CH
2
C
O
O
CH
3
+ MeSH
RN H
CH
3
OH[OH–]
k
3
O
8
[
13] kobs = k [RNH ]
A 2
Consequently, experimental eq. [13] fits the previously
mentioned situation (iii), and k can be identified as k ac-
A
1
cording to eq. [12].
In few cases, reactions were carried out at pH where
–
3
+
at pH 7.40 with [H NCH CN] = 0.002 mol dm and pH
[
RNH ]:[RNH ] ~ 9:1, and no significant changes were ob-
2
2
f
2
3
variation in the range of 6.70–8.45 at constant [NMM] =
served in slope (k ) values. Consequently, k is pH-
f
A
A
–3
–3
0
.002 mol dm and [H NCH CN] = 0.002 mol dm were car-
independent, showing no general base catalysis.
2 2 f
ried out. The kA value remained almost independent of
NMM] with a value 2.26 ± 0.04 dm mol s , while it in-
creased with [OH ] at the low [OH ] region and became in-
dependent at high [OH ] (Fig. 5). This behaviour seems to
3
–1 –1
[
Reaction with H NCH CN
f
2
2
–
–
The kinetics were performed under pseudo-first-order
–
conditions with 7 as the minor component. A plot of the
–
be a special case of Scheme 2, where only OH catalysis but
observed pseudo-first-order rate constants, kobs
,
vs.
not amine catalysis occurs, particularly at high pH. This can
be understood if eqs. [14] and [15] hold throughout the
whole concentration ranges used, and if simultaneously the
[
H NCH CN] showed upward curvatures with an increasing
2
2
f
slope (Fig. 3), while a plot of k (k = k /[H NCH CN] )
A
A
obs
2
2
f
showed an initial rapid increase in kA with the increase in
amine] followed by leveling off at higher amine concentra-
tion (Fig. 4), which is reminiscent of the reactions of 6-
H O
±
–
–
2
ratio (k3
K /k K ) [OH ] changes from <1 to >1 as [OH ]
a −1 w
[
is increased and eq. [3] changes to eq. [16].
SMe-Z with secondary amines (2). To check for a general
AH
±
k3 Ka
base catalysis in this reaction, a variation of [NMM] (NMM
[14]
[RNH ] << 2
2
AH
f
–3
k k
−1 a
is N-methylmorpholine) in the range of 0.0005–0.10 mol dm
©
2006 NRC Canada

Biswas et al.
1683
Table 1. Comparison of rate constants for the nucleophilic attack on 6-SMe-H and 7 by
nucleophiles in DMSO–H O (50:50, v/v) at 20 °C.
2
Amine or other
nucleophile
k (7)
(dm mol s )
k (6-SMe-H)
1
(dm mol s )
1
pKaAH
1
1
3
–1 –1
3
–1 –1
k (7)/k (6-SMe-H)
n-Butylamine
Methoxyethylamine
Glycinamide
10.61
9.63
8.28
5.39
17.30
17.33
138.4
65.0
26.1
2.38
3.27
5.36
2.63
1.30
0.12
0.63
25.8
24.7
22.9
20.3
5.2
Aminoacetonitrile
–
OH
–
6
–6
H O
5.52 × 10
2.80 × 10
2.0
2
–
Fig. 4. Plot of kA vs. [aminoacetonitrile] for the reaction of 7
f
Fig. 5. Plot of kobs vs. [OH ] for the reaction of 7 with
–
3
with aminoacetonitrile in DMSO–H O (50:50, v/v) at 20 °C.
2
aminoacetonitrile with [H NCH CN] = 0.002 mol dm in
2 2 f
DMSO–H O (50:50, v/v) at 20 °C.
2
AH
±
k3 Ka±
H O
2
k3 Ka
[
[
15]
[RNH ] <<
[OH− ]
2
AH
k k
k −1 Kw
−
1
a
–
LG departure from T
is rate-limiting. The very high
A
OH
A
8
k3 /k3 ratio (3.28 × 10 ) implies a rapid acid–base equilib-
k3 Ka±
H O

2

±
–
−
k 
[OH ]
rium between TA and TA followed by a rate-limiting, gen-
eral-acid-catalyzed LG departure (2). Similar observations
were encountered in the aminolysis of the electrophilic β-
methoxy-α-nitrostilbene (9-OMe) (see Chart 1) where the
deprotonation of the corresponding zwitterionic intermediate
1


k K

−1
w

16] k =
A
H O
±

2

k3
Ka
−
1
+ 

[OH ]

k K

−1
w

(
10) is fast, and methoxide ion departure is rate determining
A non-linear least-squares fit of the data to eq. [3] for
(7).
3
–1 –1
–
[
H NCH CN] gives k = 2.37 ± 0.07 dm mol
s
and
Based on the reaction in eq. [8], the reaction of OH is ex-
pected to be a diffusion-controlled proton transfer with a
k2 value around 10 dm mol
be independent of the amine basicity. k2 is also expected to
be essentially independent of the amine basicity irrespective
of whether the reaction is diffusion-controlled (K
or diffusion-separation-controlled (Ka < K ) (9). In the lat-
ter case, k2 is independent of the amine basicity because
the pK difference (K – K ) should be constant. Further-
2
2
f
1
A
–1
k /k = 50.8 ± 5.15 s . Similar treatment for the change in
[
k3 /k = 8.13 ± 0.78 × 10 s (Table 1). The k value ob-
tained from the variation of [H NCH CN] at constant pH is
almost the same as that obtained from the variation of [OH ]
at constant [NMM] and [H NCH CN] , thus confirming the
proposed mechanism.
3
–1
–
3
–1 –1
OH
10
3
–1 –1
OH
OH ] (eq. [16]) yields k = 2.48 ± 0.05 dm mol
s
and
s
(8); hence, k2 should
1
OH
8
–1
A
–1
1
2
2
f
–
AH
±
>> K )
a
a
BH
±
f
2
2
f
a
A
±
AH
a
a
a
AH
±
±
±
The rate-limiting step
more, if Ka < Ka of T , the proton transfer from T to
A A
–
The catalysis by both OH and H NCH CN demonstrates
RNH will be thermodynamically favorable and close to dif-
2
2
2
OH
A
a general base catalysis, which is most likely accounted by
Scheme 2. The lack of NMM catalysis may be attributed to
fusion controlled limit. Hence, k3 /k3 ratios should be in-
dependent of the amine basicity and have values of 5–25 (3).
Because this contrasts our experimental observation, we as-
±
its bulkiness, which precludes its closer approach to T in
A
the transition state. Either the conversion of TA± to TA or
–
cribe the very high k3 /k3 value for the H NCH CN reac-
OH
A
2
2
©
2006 NRC Canada

1
684
Can. J. Chem. Vol. 84, 2006
tion to a rate-limiting leaving group departure rather than to
Fig. 6. Brønsted Plot for the reaction of 7 with primary amines.
±
a rate-limiting proton transfer from T .
A
The nucleophilic attack step (k1)
AH
The good linearity of a Brønsted plot of log(k ) vs. pKa
1
(
β
= 0.34 ± 0.004) for the reaction of 7 with the four pri-
nuc
mary amines is shown in Fig. 6. The corresponding β for
k values for the reaction of secondary amines with 6-SMe-H
nuc
1
is 0.41. It was found that the k values for the reactions with
1
secondary amines are smaller than those for the primary
amines of comparable basicity. For example, for the 11-H–
HEPA (HEPA is N-(2-hydroxyethyl)piperazine) reaction
AH
3
–1 –1
(
pKa = 9.51), k is 1.06 ± 0.34 dm mol s , while for 11-
1
AH
H–MeOCH CH NH reaction (pK
.05 dm mol s . These results reflect a strong steric ef-
= 9.63), k is 2.63 ±
1
2
2
2
a
3
–1 –1
0
fect that reduces the reactivity of the bulkier secondary
amines. When steric effects are absent, secondary amines
generally react faster than primary amines of comparable ba-
sicity (9, 10).
tween β
and the reactivity of electrophilic olefins
(PhCH=CXY) appears to be quite general and has been ob-
served before (20).
The substitution reactions of 7 are 20–26 times faster than
nuc
±
the 6-SMe-H–RNH reactions. Hence, the formation of T
2
A
with RNH is thermodynamically more favorable for 7 than
2
for 6-SMe-H. However, based on both inductive and steric
effects a reverse trend is expected. We ascribe this discrep-
ancy to an additional effect, i.e., π-donation by the phenyl
group (Ph), which may reduce the reactivity of 6-SMe-H
Conclusions
(
11). A similar reactivity trend, which was observed for the
(
(
1) In the reactions of 7 with the more basic amines,
namely, H NCH CONH , MeOCH CH NH , and n-
reactions of H NCH CN and morpholine with the Fischer
2
2
2
2
2
2
2
2
carbene complexes 12 and 13 (see Chart 1) was attributed to
a different π-donation effect of the Ph group which lowers
the reactivity of 13 over 12 (12–15).
BuNH , no base catalysis is observed; thus, implying a
2
rate-limiting k step because of the strong electronic
1
push from the nitrogen lone pair in the product leading
to the stabilization of the transition state resulting from
the developing product resonance. For the less basic
amine, H NCH CN, general base catalysis is observed
The higher β value for 6-SMe-H–RR′NH (0.41 ± 0.01)
nuc
compared with that for the 6-SMe-H–RNH reactions
2
(
0.32 ± 0.01) (4) implies that at the transition state, C–N
2
2
bond formation is more advanced with the secondary
as the electronic push is not so prominent here.
amines. Similarly, the β value for the 7–RNH reaction
(
reaction and manifests the fact that the bond formations in
the transition states progress equally in both reactions.
nuc
2
2) The k values for 6-SMe-H–RNH reactions are lower
1
2
0.34 ± 0.02) is almost the same as that for 6-SMe-H–RNH2
than those for the 7–RNH reactions, suggesting that a
2
strong π-donation by the phenyl group reduces the reac-
tivity of 6-SMe-H.
In the reaction of 14-H with piperidine or morpholine (16)
(
eq. [17]), β (k ) = 0.14, suggesting that the C–N bond is
nuc 1
less advanced than in the reaction of 11-H and 7 with both
primary and secondary amines. This is again consistent with
the Hammond–Leffler (17, 18) principle, because 14-H (19)
Experimental section
and 15-H (16) are much more reactive, e.g., k for the 14-H-
morpholine reaction (3.19 × 10 dm mol s ) is much
Compound 7 was synthesized by following the literature
1
5
3
–1 –1
method (20). DMSO was refluxed over CaH and distilled
2
higher than k for the addition of morpholine to 11-H
under vacuum. Reagent grade amines were purchased from
Aldrich chemicals (USA). The solid amines were
recrystallized from a water–ethanol solution, and the liquids
1
3
–1 –1
(
0.49 dm mol s ), and K for the same reaction is also
1
4
3
–1
higher for 15-H (7.76 × 10 dm mol ) than for 11-H,
which is ~1.9 × 10–8 dm mol . The inverse correlation be-
3
–1
were distilled over CaH before use.
2
±
Z
Z
Z
X
Y
X
Y
k
X
–
1
.
...
H
+
RR'NH
H
C
+
C
[
17]
C
C
C
C δ
H
k
–
1
Y
δ+
RR'NH
RR'NH
1
1
4-H (CXY = Meldrum's acid moiety)
5-H (CXY = CHNO
2
)
©
2006 NRC Canada

Biswas et al.
1685
Synthesis of ␣-isobutyl-␣-(n-butylamino)methylene
Meldrum’s acid (6)
(c) S.I. Miller. Tetrahedron, 33, 1211 (1977); (d) Z.
Rappoport. Acc. Chem. Res. 14, 7 (1981); (e) Z. Rappoport.
Recl. Trav. Chim. Pays–Bas, 104, 3092 (1985); ( f ) B. A.
Shainyan. Usp. Khim. 55, 942 (1986); (g) Z. Rappoport. Acc.
Chem. Res. 25, 474 (1992); (h) T. Okuyama and G. Lodder.
Adv. Phys. Org. Chem. 37, 1 (2002).
. C.F. Bernasconi, M. Ali, K. Nguyen, V. Ruddat, and Z.
Rappoport. J. Org. Chem. 69, 9248 (2004).
. (a) C.F. Bernasconi and M.W. Stronach. J. Org. Chem. 56,
Compound 7 was prepared analogous to the procedure
reported for the synthesis of 2,2-dimethyl-5-[piperidino(p-
methoxyphenyl)methylene-1,3-dioxane-4,6-dione (21). CaCl2-
protected MeCN solution (15 mL) containing 1 mmol of
each of 7 and n-butylamine was stirred for 48 h at room
temperature. The solvent was evaporated, and the remaining
solid was recrystallized from EtOH to give α-isobutyl-α-(n-
2
3
1
993 (1991); (b) C.F. Bernasconi and M.W. Stronach. J. Am.
1
butylamino)methylene Meldrum’s acid in 35% yield. H NMR
Chem. Soc. 113, 2222 (1991).
. M. Ali, S. Biswas, Z. Rappoport, and C.F. Bernasconi. J. Phys.
Org. Chem. In press.
5. J.-C. Hallé, R. Gaboriaud, and R. Schaal. Bull. Soc. Chim. Fr.
2047 (1970).
6. C.F. Bernasconi, A.E. Leyes, Z. Rappoport, and I. Eventova. J.
Am. Chem. Soc. 115, 7513 (1993); (b) C.F. Bernasconi, A.E.
Leyes, I. Eventova, and Z. Rappoport. J. Am. Chem. Soc. 117,
(
1
300 MHz, CDCl , ppm) δ: 1.00 (2Me of i-Bu), 1.02 (Me),
3
4
.24 (CH ), 1.41 (CH ), 1.67 (2Me of Meldrum’s acid moi-
2 2
ety), 2.04 (CH of i-Bu), 2.58 (NH), 2.68 (CH of i-Bu), 3.45
2
+
+
(
2
(
CH α- to NH). ES-MS m/z: 284 (MH ), 241 (MH – CMe ),
26(MH – OCMe ), 197 (MH – HCMe –CH (CH ) ), 171
MH – i-BuN–CMe ), 114 (M – MA–CH –CH , MA is
2
2
+
+
2 2 3 2 2
+
2 2 2
Meldrum’s acid moiety).
1
703 (1995).
Kinetics and pH measurements
7. C.F. Bernasconi, J. Fassberg, R.B. Killion, Jr. and Z.
Details of the kinetic and pH measurements are reported
elsewhere (2, 4). Most reactions were followed by monitor-
ing the disappearance of the substrates around 330 nm using
a Hewlett-Packard 8453 Agilent UV–vis spectrophotometer.
Rappoport. J. Org. Chem. 55, 4569 (1990).
8. M. Eigen. Angew. Chem., Int. Ed. Engl. 3, 1 (1964).
9. W.P. Jencks. Catalysis in chemistry and enzymology. McGraw-
Hill, New York. 1969. p. 95.
0. C.F. Bernasconi, C.J. Murray, J.P. Fox, and D.J. Carre. J. Am.
Chem. Soc. 105, 4349 (1983).
1. C.F. Bernasconi, S.D. Brown, M. Ali, Z. Rappoport, H.
Yamataka, and H. Salim. J. Org. Chem. 71, 4795 (2006).
2. C.F. Bernasconi and S. Bhattacharya. Organometallics, 22, 426
1
1
1
The pH in DMSO–H O (50:50, v/v) at an ionic strength of
2
–
3
0
.50 mol dm KCl at 20 °C was determined by a digital pH-
meter (Systronics–335, India) equipped with a glass elec-
trode and a reference electrode calibrated with standard aq.
buffers in DMSO–H O (50:50, v/v) before use. Stock solu-
2
(
2003).
tions of the substrates were prepared in anhyd. acetonitrile.
–
1
13. M. Ali. New J. Chem. 28, 412 (2004).
The pseudo-first-order rate constants (kobs, s ) were ob-
tained by fitting the kinetic traces with a suitable computer-
fit program and the results were within an error limit of
1
1
4. M. Ali and D. Maiti. J. Organeomet. Chem. 689, 3520 (2004).
5. M. Ali, S. Gangopadhyay, and M. Mizanuddin. J. Organomet.
Chem. 690, 4878 (2005).
6. C.F. Bernasconi and M. Panda. J. Org. Chem. 52, 3042 (1987).
7. G.S. Hammond. J. Am. Chem. Soc. 77, 334 (1955).
±5%.
1
1
Acknowledgment
18. J.E. Leffler and E. Grunwald. Rates and equilibria of organic
reactions. Wiley, New York. 1963. p. 156.
This work was supported by grants SR/S1/IC-19/2002
from the Department of Science and Technology (DST),
New Delhi and F.12–22/2003(SR) from University Grant
Commission (UGC), New Delhi.
1
9. C.F. Bernasconi, R.F. Renfrow, and P.R. Tia. J. Am. Chem.
Soc. 108, 454 (1986).
2
2
0. C.F. Bernasconi. Tetrahedron, 45, 4017 (1989).
1. M. Beit-Yannai and Z. Rappoport. J. Chem. Soc., Perkin
Trans. 2. 1534 (2001).
References
1
. For reviews, see: (a) Z. Rappoport. Adv. Phys. Org. Chem. 7,
(1969); (b) G. Modena. Acc. Chem. Res. 4, 73 (1971);
1
©
2006 NRC Canada