Mechanistic evidence for an α-oxoketene pathway in the formation of β-ketoamides/esters via Meldrum's acid adducts

Article abstract of DOI:10.1021/ja046488b

A practical, one-pot process for the preparation of β-keto amides via a three-component reaction, including Meldrum's acid, an amine, and a carboxylic acid, has been developed. Key to development of an efficient, high-yielding process was an in-depth understanding of the mechanism of the multistep process. Kinetic studies were carried out via online IR monitoring and subsequent principal component analysis which provided a means of profiling the concentration of both the anionic and free acid forms of the Medrum's adduct 6 in real time. These studies, both in the presence and absence of nucleophiles, strongly suggest that formation of β-keto amides from acyl Meldrum's acids occurs via α-oxoketene species 2 and rule out other possible reaction pathways proposed in the literature, such as via protonated α-oxoketene intermediates 3 or nucleophilic addition-elimination pathways.

Full text of DOI:10.1021/ja046488b

Published on Web 09/16/2004
Mechanistic Evidence for an r-Oxoketene Pathway in the
Formation of â-Ketoamides/Esters via Meldrum’s Acid
Adducts
Feng Xu,*,† Joseph D. Armstrong III,* George X. Zhou,*,‡ Bryon Simmons,
,†
†
†
‡
†
David Hughes, Zhihong Ge, and Edward J. J. Grabowski
Contribution from the Departments of Process Research and Analytical Research,
Merck Research Laboratory, Rahway, New Jersey 07065
Received June 14, 2004; E-mail: feng_xu@merck.com
Abstract: A practical, one-pot process for the preparation of â-keto amides via a three-component reaction,
including Meldrum’s acid, an amine, and a carboxylic acid, has been developed. Key to development of an
efficient, high-yielding process was an in-depth understanding of the mechanism of the multistep process.
Kinetic studies were carried out via online IR monitoring and subsequent principal component analysis
which provided a means of profiling the concentration of both the anionic and free acid forms of the Medrum’s
adduct 6 in real time. These studies, both in the presence and absence of nucleophiles, strongly suggest
that formation of â-keto amides from acyl Meldrum’s acids occurs via R-oxoketene species 2 and rule out
other possible reaction pathways proposed in the literature, such as via protonated R-oxoketene
intermediates 3 or nucleophilic addition-elimination pathways.
Introduction
â-Keto esters and amides are versatile intermediates in organic
synthesis and often are prepared from acyl Meldrum’s acid
1
adducts. This method involves reaction of Meldrum’s acid with
activated carboxylic acids followed by decarboxylation in the
presence of nucleophiles such as alcohols or amines (Scheme
Figure 1. Possible reaction intermediates proposed in the literature.
1). The ability of readily available acyl Meldrum’s acids adducts
Scheme 1 . Preparation of â-Keto Esters and Amides from Acyl
Meldrum’s Acids
to react with various nucleophiles allows quick access to a
variety of functionalized compounds. Application of this
methodology in synthetic chemistry has been widely exploited;
1
-4
however, the mechanism is not well understood.
Four
tentative reaction pathways have been proposed: (1) nucleo-
5
philic addition-elimination pathway via intermediate 1; (2)
9
(
0
259 °C) or under flash vacuum pyrolysis condition (600 °C,
3,5b,6
formation of R-oxoketene 2;
(3) formation of protonated
R-oxoketene 3; and (4) reaction via intermediate 4 (Figure 1).
R-Oxoketenes 2 have been the focus of numerous theoretical
and experimental studies. They have been observed by ther-
1
0,11
1
.01 Torr).
In light of these studies, 2 has been suggested
2
6a,7
as a possible intermediate in reactions in which acyl Meldrum’s
acid adducts react with amines, alcohols, and imines, etc.,
although the alternative pathway through nucleophilic addition
8
molysis of Meldrum’s acid derivatives in boiling diphenyl ether
5b,6
to intermediate 1 followed by elimination cannot be excluded.
†
Department of Process Research.
Department of Analytical Research.
(
6) For additional examples, see: (a) Yamamoto, Y.; Watanabe, Y.; Ohnishi,
S. Chem. Pharm. Bull. 1987, 35, 1860-1870. (b) Sato, M.; Ogsawara, H.;
Yoshizumi, E.; Kato, T. Chem. Pharm. Bull. 1983, 31, 1902-1909. (c)
Sato, M.; Ogsawara, H.; Yoshizumi, E.; Kato, T. Heterocycles 1982, 17,
297-300.
‡
(
1) For reviews, see: (a) Far, A. D. Angew. Chem., Int. Ed. Engl. 2003, 42,
2
340-2348. (b) Gaber, A. E. M.; McNab, H. Synthesis 2001, 2059-2074.
(
c) Chen, B. C. Heterocycles 1991, 32, 529-597. (d) Huang, X. Youji
Huaxue 1986, 329-334.
(7) (a) Hamilakis, S.; Kontonassios, D.; Sandris, C. J. Heterocycl. Chem. 1996,
33, 825-829. (b) Sato, M.; Takayama, K.; Abe, Y.; Furuya, T.; Inukai,
N.; Kaneko, C. Chem, Pharm. Bull. 1990, 38, 336-339. (c) Yamamoto,
Y.; Watanabe, Y. Chem. Pharm. Bull. 1987, 35, 1871-1879.
(8) For recent reviews, see: (a) Tidwell, T. T. Ketenes; John Wiley & Sons:
New York, 1995. (b) Wentrup, C.; Heilmayer, W.; Kollenz, G. Synthesis
1994, 1219-1249. (c) Tidwell, T. T. Acc. Chem. Res. 1990, 23, 273-279.
(9) Cassis, R.; Tapia, R.; Valderrama, J. A. Synth. Commun. 1985, 15, 125-
133.
(10) Gordon, H. J.; Martin, J. C.; McNab, H. J. Chem. Soc., Chem. Commun.
1983, 957-958.
(11) Bibas, H.; Kappe, C. O.; Wong, M. W.; Wentrup, C. J. Chem. Soc., Perkin
Trans. 2 1998, 493-498.
(
(
(
2) Emtenas, H.; Alderin, L.; Almqvist, F. J. Org. Chem. 2001, 66, 6756-
6
761.
3) Emtenas, H.; Soto, G.; Hultgren, S. J.; Marshall, G. R.; Almqvist, F. Org.
Lett. 2000, 2, 2065-2067.
4) The mechanism involving acyl Meldrum’s acids in solution was never
clarified. It is often to have several proposed reaction pathways in the same
publication.
(
5) For examples, see: (a) Pak, C. S.; Yang, H. C.; Choi, E. B. Synthesis 1992,
1
213-1214. (b) Svetlik, J.; Goljer, I.; Turecek, F. J. Chem. Soc., Perkin
Trans. 1 1990, 1315-1318. (c) Sato, M.; Yoneda, N.; Katagiri, N.;
Watanabe, H.; Kaneko, C. Synthesis 1986, 672-674. (d) Oikawa, Y.;
Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978, 43, 2087-2088.
13002
9
J. AM. CHEM. SOC. 2004, 126, 13002-13009
10.1021/ja046488b CCC: $27.50 © 2004 American Chemical Society

Formation of
â
-Ketoamides/Esters via Meldrum’s Acid Adducts
A R T I C L E S
Almqvist et al. suggested that formation of â-lactams12 is a [2
3
Scheme 2. Preparation of â-Keto Amide 8
+
2] product of R-oxoketene 2 and a thiazoline. Subsequently,
13
they also proposed that 2-pyridinone is formed through
protonated ketene intermediate 3 when branched imines are
subjected to the same reaction conditions as for the preparation
2
of â-lactams. However, other literature examples suggest
pathways not involving 2 are also viable. For example,
pyranones can be prepared via [2 + 4] addition of vinyl ethers
1
4
with R-oxoketenes 2 generated by thermolysis of dioxinones.
In contrast, treatment of acyl Meldrum’s adducts with vinyl
ethers (benzene, 80 °C) results in formation of pyrandiones
14
rather than pyranones. Similarly, ketone-exchanged products,
6a
1
,3-oxozinediones, are formed when acyl Meldrum’s acids are
treated with cyclohexanone in refluxing benzene. Apparently,
reaction pathways other than via R-oxoketene 2 are involved
to form pyrandiones14 as well as 1,3-oxazinediones since
decarboxylation does not occur during the reaction. Yamamoto
et al. proposed that the intermediate 4 or its zwitterionic
tautomers could be responsible for the formation of 1,3-
oxazinones while also suggesting that acyl Meldrum’s adducts
are a good source of R-oxoketene 2. Given that these reactions
are poorly understood and to improve the versatility and
efficiency of these reactions, we undertook a detailed mecha-
nistic study to better define the reaction pathway and to gain
insight on the factors which influence the reaction.
6a
carboxylic acid activation, reaction of the activated acid with
Meldrum’s acid, followed by reaction with the amine and
decarboxylation. After preliminary optimization, 6 was prepared
by adding 1.1-1.2 equiv of pivaloyl chloride to a solution of
Meldrum’s acid, the carboxylic acid 5, catalytic DMAP, and
i-Pr2NEt in dimethylacetamide (Me2NAc) or MeCN as solvent,
at ambient temperature followed by warming to 55 °C.
Preliminary studies indicated 6 was unstable in acidic media at
ambient temperature but was quite stable in basic solution.
To overcome the instability of the free acid of 6 which would
occur upon attempted isolation, a one-pot process to prepare 8
was required. However, when 6 was formed in the presence of
6
a
1
5
Results and Discussion
In conjunction with a recent drug development program, we
required an efficient preparation of â-keto amide 8, which we
envisioned could be accomplished via coupling of the three
readily available components as shown in Scheme 2. In the first
part of this section, we describe the design and development of
a process to prepare 8 in an efficient, one-pot process. The
observations made during the development of this process
provided the basis for an in-depth examination of the mecha-
nistic aspects of the reaction, which are detailed in the latter
part of this section. The combination of online IR monitoring
and principal component analysis made it possible to profile
the concentration of both the anionic and free acid forms of the
Meldrum’s adduct 6 in real time for kinetic studies, which
provided a critical tool for delineating the mechanism of this
complex reaction sequence.
3
equiV of i-Pr2NEt in 95% yield, and treated directly with 1.0
equiV of triazole HCl salt 7, the decarboxylation/aminolysis
reaction was slow and stalled at about 80% conVersion. This
was remedied by reducing the amount of i-Pr2NEt to 2.1 equiv,
which is sufficient to neutralize the HCl and adduct 6 (pKa )
1
6
3
.1) generated during the reaction, but not t-BuCO2H (pKa )
.0), which has the highest pKa of the three acids formed during
5
the reaction. Under these conditions, we found that formation
of 6 still performed well (95% yield, 97% conversion) and the
decarboxylation/aminolysis now proceeded smoothly at 70 °C
to achieve 98% conversion within 6 h after 1 equiv of triazole
HCl salt 7 was added. However, the overall reaction process is
quite sensitive to the initial i-Pr2NEt charge since the base has
opposing effects on the two steps. The rate of decarboxylation
decreases as the initial base charge increases. If the base charge
is <1.9 equiv, formation of 6 suffers from conversion and yield,
while the decarboxylation is very fast and reaches com-
pletion within 2 h at 70 °C and the overall yield for the
two steps is reduced to <85%. If the base charge is >2.2
equiv, >98% conversion for formation of 6 can be achieved,
while the decarboxylation is slow and cannot reach full
conversion at 70 °C. Thus, the amount of base must be carefully
balanced (2.0-2.1 equiv) to achieve maximum conversion and
yield.
One-Pot, Three-Component Coupling and Key Observa-
tions. The synthetic process to couple the carboxylic acid 5,
Meldrum’s acid, and the triazole 7 consists of three key steps:
(12) Cf. ref 3.
Acid Effects in the One-Pot Process. The observations
outlined above suggested the decarboxylation/amination reaction
required a somewhat acidic medium for optimum results.
Likewise, a careful review of literature reports for the prepara-
tion of â-keto amides revealed that the amine component was
(13) Cf. ref 2.
(
15) It is known that acyl Meldrum’s acids are not always stable. For example,
see ref 5b.
(14) Zawacki, F. J.; Crimmins, M. T. Tetrahedron Lett. 1996, 37, 6499-6502.
(16) Measured by titration in water at ambient temperature.
J. AM. CHEM. SOC.
9
VOL. 126, NO. 40, 2004 13003

A R T I C L E S
Xu et al.
Scheme 3. Possible Pathways for Self-Decomposition18
always undercharged relative to the acyl Meldrum’s acid
intermediate, again suggesting that slightly acidic conditions
might be beneficial. Several acids of varying pKa were screened
5
to understand the role of acidity on decarboxylation. Acids with
pKa of <3.5, including HCl, MeSO3H, CF3CO2H, and 2-O2N-
and 3-O2N-C6H4CO2H, afforded conversions of >95% within
6
h at 55 °C. The weaker acids HOAc and t-BuCO2H gave
conversions of only 61% and 20%, respectively. Thus, acids
that can protonate adduct 6, which has an aqueous pKa of 3.1,
are effective in promoting rapid reaction, suggesting the free
acid form of 6 is the reactive intermediate.
The reaction was further optimized with CF3CO2H (TFA)
chosen as an acid having appropriate acidity. The optimized
protocol involves formation of 6 with pivaloyl chloride and
Meldrum’s acid and the addition of 7, followed by addition of
TFA, typically 0.3 equiv. In this way, the significant aminolysis
rate Variation caused by the slight changes in i-Pr2NEt charge
is minimized after the TFA “pH adjustment”. Finally, the
decarboxylation/aminolysis reaction is carried out at lower
temperature (50 °C Vs the preVious 70 °C).17
For pathway A, the reaction rate constants will be unaffected
by added acid or base, as shown in eqs 1 and 2.
slow
HA
8 2 + Me CO + CO
(1)
(2)
2
2
k
rate ) k[HA]
These noteworthy observations made during process develop-
ment prompted us to study the reaction in more detail. In the
mechanistic studies described below, we provide conclusive
evidence that the reaction of Meldrum’s acid adducts such as 6
proceed via an R-oxoketene pathway. The mechanistic work is
divided into two major sections: kinetic studies and model
studies.
For pathway B, the following equations apply:
K1
+
-
2
HA y
\
z H A + A
(3)
(4)
2
slow
+
H A
8 3 + Me CO + CO
2
2
2
k
2
K [HA]
+
1
Kinetic Studies on Self-Decomposition of Acyl Meldrum’s
Adduct 6. Our kinetic studies began with an investigation of
the decomposition of 6 in the absence of an added nucleophile,
which can proceed either via the neutral compound (path A,
Scheme 3) or the protonated species (path B, Scheme 3). As
discussed below, these pathways can be distinguished based on
[
H A ] )
2
-
[A ]
+
rate ) k[H A ]
2
2
kK [HA]
1
18
)
(5)
the response of the kinetics to added acid or base.
-
[
A ]
(
17) One-pot process procedure: 2,4,5-Trifluorophenylacetic acid (5, 2.5 kg,
+
-
+
In the absence of acid or base, [H2A ] ) [A ]. Thus, [H2A ]
) (K1) [HA]. Therefore
1
1
3.15 mol), Meldrum’s acid (2.09 kg, 14.46 mol), and DMAP (128.5 g,
.052 mol) were charged into a 50 L three-neck flask. Acetonitrile (7.5 L)
1
/2
was added in one portion at room temperature. N,N-Diisopropylethylamine
(4.92 L, 28.27 mol) was added in portions at room temperature while
+
1/2
maintaining the temperature below 50 °C. Pivaloyl chloride (1.78 L, 14.46
mol) was added dropwise over 1-2 h while maintaining the temperature
below 55 °C. The reaction was aged at 45-50 °C for 2-3 h. Triazole
hydrochloride 7 (3.01 kg, 13.2 mol) was added in one portion at 40-50
rate ) k[H A ] ) k(K ) [HA]
(6)
2
1
If <1 equiv of base B is added to the system, A- would
increase and lead to a reduced rate (eq 5).
°
C. Trifluoroacetic acid (303 mL, 3.95 mol) was added dropwise, and the
reaction solution was aged at 50-55 °C for 6 h. 90% solution assay yield
of 8. This process has been successfully and reproducibly demonstrated in
3
-
+
00 kg scales.
HA + B h A + HB
(7)
(
18) To have a less complicated consideration, all the tautomers, rotamers, as
well as resonance structures are not specifically considered here. For
example, although the following equilibriums can be included in the kinetic
In the presence of a strong acid the equilibrium (eq 3) is
shifted and [H2A ] is increased. Therefore, the reaction rate
2
-
analyses, the outcome reaction rate can be expressed as: kK
1
K
3
[HA] /[A ]
+
2
for pathway B and kK [HA] for pathway A, which result in the same kinetic
-
effects on [HA] or [A ] as described in the text.
would increase.
In addition, protonation of ketenes has been studied both
8
,19
theoretically and experimentally.
The preferred protonation
of ketene is at Câ to afford the acylium ion 9 instead of 3. In
the gas phase, 9 is lower in energy than the R-protonated ketene
8
,19-21
3
.
It is unlikely that 3 can be formed through direct
protonation of 2 via pathway C since this process has a high
energy barrier and 3 is disfavored thermodynamically.21
(
19) For leading references, see: (a) Gong, L.; McAllister, M. A.; Tidwell, T.
T. J. Am. Chem. Soc. 1991, 113, 6021-6028. (b) Lien, M. H.; Hopkinson,
A. C. J. Org. Chem. 1988, 53, 2150-2154. (c) Armitage, M. A.; Higgins,
M. J.; Lewars, E. G.; March, R. E. J. Am. Chem. Soc. 1980, 102, 5064-
5068.
To have more focused discussion in the text, detailed kinetic analyses of
all other possible mechanisms, which can be done as described in the text,
are not listed here.
13004 J. AM. CHEM. SOC.
9
VOL. 126, NO. 40, 2004

Formation of
â
-Ketoamides/Esters via Meldrum’s Acid Adducts
A R T I C L E S
-
Figure 2. Extracted spectra of the free acid (HA) and anion (A , i-Pr2NEt
salt) of 6 obtained in Me2NAc.
Figure 3. Self-decomposition of the free acid 6 in Me2NAc. Plots of
concentration of HA vs time: (a) 6 itself at 51.5 °C; (b) in the presence of
At this point, it became clear that the capability to obtain
the kinetic profile of the free acid 6 as well as its anionic form
was essential to understand the reaction pathway. Therefore,
attempts to quantify the free acid and its anionic form in solution
by applying online IR techniques were initiated. Titration with
i-Pr2NEt showed that the free acid 6 was stoichiometrically
converted to its anionic form as expected on the basis of the
several unit differences of pKa’s between 6 and i-Pr2NEt.
Although the IR spectra of the free acid 6 and its anion are
substantially different, the overlapping peaks in the online IR
spectra obtained during a reaction or titration are very subtle
and make obtaining the kinetic profiles of the free acid 6 and
its anion quite difficult. To fully distinguish each component
in the complex mixture, a more sophisticated data analysis
method had to be applied in order to resolve each component
over the entire reaction period.
0
4
.5 equiv of TFA at 48.3 °C; (c) in the presence of 1.0 equiv of TFA at
8.8 °C; (d) in the presence of 0.5 equiv of i-Pr2NEt at 52.5 °C.
Table 1. Measured kobs’s in Me2NAc with Isolated 6
10-
4
T
yieldc
(%)
k
obs
×
entry
substrates
additive
(s-1)
(°C)
1
2
3
4
5
6
7
8
9
BocNHOBoca
BocNHOBocb
n-PrOH
3.93
3.35
4.18
4.04
4.78
1.14
4.81
17.0
4.09
4.37
4.37
4.68
50.8 10, 78
50.1 10, 78
51.0 11, 97
50.8 12, 92
PhNH2
e
piperidine
50.9 13, 78
d
7
41.1 8, 91
51.4 8, 91
61.8 8, 90
51.5
48.3
48.8
d
7
d
7
none
none
none
none
none
10
TFA (0.5 equiv)
TFA (1.0 equiv)
i-Pr2NEt (0.5 equiv)
1
1
1
2
52.5
The method we chose was principal component analysis, an
algorithm that has been used to extract chemical and process
a
b
2
equiv of BocNHOBoc was used. 1 equiv of BocNHOBoc was used.
c
Isolated yield. Free base. e 13 (R ) 2,4,5-trifluorobenzyl) )
d
22,23
information from reaction spectra.
To extract the spectra of
both free acid 6 and its anionic form, principal component
analyses were first performed on the titration spectra of free
acid 6 with i-Pr2NEt, using ConCIRt (version 2, from ASI
Applied Systems, Millersville, MD). After several attempts,
optimal spectral regions (1800-1680, 985-875, and 725-675
cm ) containing major spectral features of both acid 6 and its
anion, and having the least interferences by other coexisting
species, were identified. The component spectra of the free acid
of HA and A- in the reaction system became possible by
feeding/using the above extracted spectra (Figure 2).
With an analytical method in hand, kinetic studies were
initiated. Due to the solubility limitation of 6 in acetonitrile,
the self-decomposition kinetic studies were studied first by using
-
1
isolated adduct 6 in a homogeneous Me NAc solution, which
2
6
and its anion within these three optimal regions were obtained
provided a simplified system by eliminating all the acid-base
equilibria that exist in the one-pot process solution. As
mentioned above, preparation of 8 is equally effective in either
and are illustrated in Figure 2. Peaks at 704.3, 922.3, and 1739.4
cm represent the free acid 6 while peaks at 702.3, 947.7, and
1
-
1
717.6 cm- correspond to the anionic form of 6. Thus,
1
24
MeCN or Me NAc. As shown in Figures 3 and S1 (Supporting
2
quantitative monitoring of the real time concentration change
Information), a first-order dependence in the acid form 6 (HA)
-
4
-1
was clearly observed, with a kobs of 4.09 × 10
s .
(
20) (a) Birney, D. M. J. Org. Chem. 1994, 59, 2557-2564. (b) Tortajada, J.;
Berthomieu, D.; Morizur, J.-P.; Audier, H.-E. J. Am. Chem. Soc. 1992,
In addition, the kinetic profiles for the self-decomposition of
1
14, 10874-10880. (c) Leung-Toung, R.; Peterson, M. R.; Tidwell, T. T.;
6 in the absence/presence of TFA or i-Pr2NEt (Figure 3; Table
Csizmadia, I. G. J. Mol. Struct. 1989, 183, 319-330. (d) Bouchoux, G.;
1, entries 9-12) indicate that acid or base have almost no effect
Hppilliard, Y. J. Phys. Chem. 1988, 92, 5869-5874.
3 2
21) ) As reported, 43 kcal/mol gap exists between CH dCd
CtO+ and CH
(
on the rate constants. The observed first-order kinetics in HA
only, along with the lack of catalysis by TFA, allowed us to
rule out the pathway via protonated ketene 3 for the decomposi-
+
O H. See: (a) Nobes, R. H.; Bouma, W. J.; Radom, L. J. Am. Chem. Soc.
1
983, 105, 309-314. (b) Vogt, J.; Williamson, A. D.; Beauchamp, J. L. J.
Am. Chem. Soc. 1978, 100, 3478-3483.
(
22) Malinowski, E. H.; Howery, D. G. Factor Analysis in Chemistry; John
Wiley & Sons: New York, 1980.
2
5
tion of acyl Meldrum’s adducts.
(23) Cameron, M.; Zhou, G. X.; Hicks, M. B.; Antonucci, V.; Ge, Z.; Lieberman,
D. R.; Lynch, J. E.; Shi, Y.-J. J. Pharm. Biomed. Anal. 2002, 28, 137-
Kinetic Evidence against Nucleophilic Addition-Elimina-
tion Mechanism. Based on the kinetics described above, the
self-decomposition of 6 is consistent with reaction via an
R-oxoketene intermediate. However, for reactions in the pres-
1
44.
(
24) The obtained online IR kinetic profiles of the combination of anion and
free acid form of 6 as well as the formation of the product matched very
well with the HPLC kinetic profile as shown later on in Figure 7.
J. AM. CHEM. SOC.
9
VOL. 126, NO. 40, 2004 13005

A R T I C L E S
Xu et al.
Scheme 4. Possible Nucleophilic Addition-Elimination Pathway18
Figure 4. Plots of concentration of acid form HA in Me2NAc vs time:
(
a) in the presence of 1.0 equiv of BocNHOBoc at 50.1 °C; (b) in the
presence of 2.0 equiv of BocNHOBoc at 50.8 °C.
ence of a nucleophile, the nucleophilic addition-elimination
through intermediates such as D1 or D2, formed from HA or
H2A , could become the preferred pathway (Scheme 4). Given
order kinetics in HA do not support the nucleophilic addition-
elimination mechanism and are consistent with a pathway via
the oxo-ketene 2 (Figure 4).
+
that proton exchange steps are fast, the addition-elimination
step or possibly the following fragmentation of D1 or D2 would
likely be the rate-determining step. Reaction rates or kobs’s
should be different if nucleophilic addition was involved in the
reaction or if fragmentation of an intermediate already incor-
porating the nucleophile was the rate-limiting step.
These studies were extended with aniline, piperidine, triazole
free base 7, and n-propanol as nucleophiles. Note that aniline
and triazole 7 (pKa ) 4.0 in water ) have similar pKa’s.
Introduction of an undercharge of a basic nucleophile such
as an amine introduces a new fast acid-base equilibrium (eq
8)
1
6
As outlined above, isolated acyl Meldrum’s adducts react with
amines to afford the corresponding â-ketoamides. More interest-
ingly, nonbasic amine derivatives, such as carbamates, amides,
and hydroxylamines,28 as well as alcohols, can also react with
these adducts to effectively provide the corresponding 1,3-
dicarbonyl compounds. To investigate the effect of the nature
of the nucleophile, we selected a variety of basic and nonbasic
nucleophiles as reaction partners. We initiated these studies with
BocNHOBoc since it is nonbasic and is a much weaker bulky
nucleophile than the triazole 7. Comparison of the kobs’s with
other weak or strong nucleophiles would reveal whether
nucleophilic addition or the following elimination is involved
in the rate-determining step.
-
+
HA + Nu h A + HNu
(8)
26
27
In this case, [HA] is constant before most of Nu is consumed
vide infra). Therefore, eqs 2 and 5 would result in different
kinetic profiles. As outlined above, the anionic form A is very
stable and will not react with amines. Negative first-order
kinetics in A would be observed if a protonated R-oxoketene
is involved in the main reaction pathway. Otherwise, given that
the acid-base equilibrium is rapid, pseudo-zero-order in [A ]
would be expected. Online IR to probe the reaction kinetic
3
1
(
-
-
-
profiles again became our tool of choice to differentiate the
concentration changes of the anionic form A and the free acid
-
form HA during the reaction.
Thus, 6 was treated with 1 or 2 equiv of BocNHOBoc in
2
9
Use of n-propanol (Figure 5a) resulted in first-order kinetics
in HA, which was identical to the kinetics observed with the
carbamate BocNHOBoc. Use of the triazole 7, aniline, or
piperidine resulted in pseudo-zero-order kinetics in A . As
shown in Figure 5b, the observed concentration profile of the
free acid form HA is almost unchanged until the majority of
the anionic form A is consumed, due to the rapid acid-base
proton exchange (eq 8). Triazole 7, aniline, piperidine, n-PrOH,
and BocNHOBoc all gave very similar kobs’s, which closely
matched those measured for the self-decomposition of 6. The
kobs’s (Table 1) further confirmed that nucleophiles such as
amines, alcohols, carbamates, etc. do not react directly with HA
or H2A . The fact that the reaction rate is zero order in A in
the presence of amine nucleophiles (piperidine, aniline, 7) also
implies that the main reaction pathway is through an R-oxo-
ketene rather than a protonated R-oxoketene intermediate.
Kinetic studies were also carried out at different reaction
temperatures (Table 1, entries 6-8) to determine the activation
Me2NAc at 50 °C for 4 h to give 10 in 70% yield. Kinetic
studies were carried out by online IR. As shown in Figures 4
and S2 (Supporting Information), first-order kinetics in the free
acid 6 and zero-order in BocNHOBoc were clearly observed.
The yield and rate were almost identical when 1 or 2 equiv of
BocNHOBoc was used. The kobs’s (Table 1, entries 1-2) are
very close to those measured for the self-decomposition of 6,
in which the rate-determining step is likely the formation of
-
-
3
0
R-oxoketene 2. To conclude, the kobs’s and the observed first-
(
25) A stepwise formation of the oxo-ketene by loss of acetone to form
intermediates such as 4, followed by decarboxylation, cannot be ruled out.
The fact that the reaction rate is unaffected by the increasing concentration
of acetone formed during the reaction provides some evidence against the
+
-
6
a
pathway via intermediates such as 4, if reversible formation of these
intermediates is the rate-determining step.
(
(
(
26) Sorensen, U. S.; Falch, E.; Krogsgaard-Larsen, P. J. Org. Chem. 2000, 65,
1
003-1007.
27) Yamamoto, Y.; Ohnishi, S.; Azuma, Y. Chem. Pharm. Bull. 1982, 30,
505-3512.
28) Mohri, K.; Oikawa, Y.; Hirao, K.-I.; Yonemitsu, O. Chem. Pharm. Bull.
3
1
982, 30, 3097-3105; Heterocycles 1982, 19, 515-520, 521-524.
(
(
29) Similar yields were reported in the literature for other substrates.
30) Shelkov, R.; Nahmany, M.; Melman, A. J. Org. Chem. 2002, 67, 8975-
(31) For more detailed discussions, see “Kinetic profile in the ‘real’ one-pot
solution” section.
8
982.
13006 J. AM. CHEM. SOC.
9
VOL. 126, NO. 40, 2004

Formation of
â
-Ketoamides/Esters via Meldrum’s Acid Adducts
A R T I C L E S
Figure 5. Plots of concentration of free acid and anion forms of 6 and products in Me2NAc vs time. Reaction conditions: (a) n-PrOH at 51.0 °C; (b) aniline
at 50.8 °C.
Scheme 5. Acid-Base-Salt Turning Cycle in the One-Pot
Process
q
energies. In Me2NAc, ∆G obs ) 23.9, 24.0, 24.1 kcal/mol at
q
6
1.8, 51.4, and 41.1 °C, respectively. ∆H obs was 27.1 kcal/
q
q
mol and ∆S obs was 9.6 ( 1 eu. The observed positive ∆S obs
in Me2NAc clearly shows that a dissociative transition state is
involved during the decarboxylation of acyl Meldrum’s adducts.
This is consistent with the hypothesis that the rate-determining
step is formation of R-oxoketene rather than an intermolecular
nucleophilic addition-elimination mechanism.
Figure 6. Plot of concentration of the acid form of 6 vs time for self-
decomposition of 6 in MeCN process solution at 49.5 °C.
Table 2. Measured kobs’s in MeCN Process Solutiona
Kinetic Profile in the Process Solution. Finally, the kinetic
profiles in the process solution used for the synthetic reaction
were examined. In these experiments, amine HCl salts were
used. As mentioned above, 1 equiv of t-BuCO2H and 1 equiv
of HCl are formed during the formation of 6. The 2 equiv of
i-Pr2NEt charged at the beginning of the reaction is thus used
to neutralize the 1 equiv of HCl and 1 equiv of free acid 6 to
their corresponding salts. Maintaining 6 as its anion form is
one of the keys to making this process robust by minimizing
its decomposition, since 6 remains as its anionic form in the
solution until a catalytic amount of TFA is added. TFA pro-
vides the proton source to partially convert the anionic form of
4
yieldc (%)
entry
substrates
k
obs
×
10- (s-1)
T (°C)
1
2
3
4
5
6
PhNH2b
2.93
2.74
3.30
2.13
2.16
1.48
48.5
49.5
49.6
49.5
49.5
49.5
12, 92
8, 91
8, 90
b
7
b,d
7
e
none
nonee
nonee
a
Unless otherwise mentioned, a process stock solution of 6 was prepared
from 1.0 equiv of Meldrum’s acid, 2.15 equiv of i-Pr2NEt, 1.1 equiv of
pivaloyl chloride, and 0.08 equiv of DMAP. 0.3 equiv of TFA was charged
after HCl salt 7 or aniline HCl salt was added. b HCl salt. Assay yield
c
d
calculated by HPLC using an external reference standard. 0.5 equiv of
TFA was charged. e Self-decomposition of 6 in the process MeCN solution
6
to its free acid while TFA in turn is converted to its
by stepwise addition of TFA: entry 4, with first 0.3 equiv of TFA addition;
entry 5, with second 0.3 equiv of TFA addition; entry 6, with last 0.6 equiv
of TFA addition.
carboxylate salt. As the decarboxylation of 6 proceeds, the
triazole HCl salt 7 is converted to amide 8 while the liberated
+
-
H converts the anionic form of 6 to its free acid form. With
first order in [HA] and zero in [A ] (Figure S7, Supporting
this overall acid-base-salts turnover cycle (Scheme 5) in mind,
the outcome of the kinetic results for the real process can be
readily understood.
Information). The kobs’s measured at each of the three TFA
charge stages are listed in Table 2 (entries 4-6).
Figure 7 shows the kinetic profile under the actual process
conditions. The reaction profile (combination of the anion and
free acid of 6 vs time) obtained by HPLC analysis also matched
the online IR data. Again, use of online IR coupled with
principal component analysis provided the means to profile HA
The requirement of 1 full equiv of TFA to complete the self-
decomposition of 6 in the process solution confirms the acid-
base turnover cycle. Addition of TFA converts the anion form
of 6 into its free acid which initiates decomposition. NMR
analyses of the decomposed products indicated that polymers
or oligomers were formed. The reaction profile by online IR
clearly showed that 6 decomposed after aliquots of TFA were
introduced sequentially (Figure 6). Kinetic analysis indicated
-
and A during the reaction. Formation of the free acid form 6
(HA) was immediately observed upon addition of a catalytic
amount of TFA. This clearly shows that constant liberation of
the free acid form HA through a fast acid-base proton exchange
J. AM. CHEM. SOC.
9
VOL. 126, NO. 40, 2004 13007

A R T I C L E S
Xu et al.
Table 3. Preparation of Diphenol 15 and 16a
ratio of
entry
conditions
15/16
yield (%)
b
1
2
14, TFA (1 equiv), 55 °C, 3 h
>98:2
7.4:1
15, 70
c
14, TFA (0.5 equiv), Et3N‚HCl (1 equiv),
15 + 16, 70
55 °C, 3 h
3
4
14, 55 °C, 1 h
8:1
0.9:1
0:100 16, 72
4:1
4
2
.5 h
4 h
b
15, TFA (0.5 equiv), Et3N‚HCl (1 equiv),
5 °C, 24 h
15, TFA (0.5 equiv), 24 h
Figure 7. Plots of concentration of the free acid and anion forms of 6 and
5
8
in MeCN process solution vs time. Reaction conditions: 0.3 equiv of
5
98:2
-
TFA and 1.0 equiv of triazole HCl salt 7 at 49.5 °C. [HA] plus [A ]: dashed
line is based on online IR data. Circles are obtained by HPLC analyses.
For the reaction sequence, see Scheme 5.
a
The main purpose of adding TFA or triethylamine HCl salt is to mimic
the one-pot process conditions. b Isolated yield. c Assay yield calculated by
HPLC using an external reference standard.
during the reaction is the key to achieve high conversion
(>99%). This is also consistent with the observed variation in
that malonate derivatives can be used as acylating reagents with
decarboxylation rate and conversion if TFA is not introduced
into the reaction system since any excess base would prevent
complete conversion to the free acid form.
Under process conditions, the decarboxylation is pseudo zero
order in the anionic form 6, which is the same as when isolated
aromatic compounds via Friedel-Crafts-type reactions under
3
3
acidic conditions. Most likely, this type of reaction occurs
through a protonated intermediate. To probe the existence of
protonated acyl Meldrum’s adducts, compound 14 was prepared
and subjected to decarboxylation in the absence of an external
nucleophile.
6
is treated with free amine nucleophiles in Me2NAc. The
reaction rate increases as more TFA is charged, because the
initial concentration of HA is increased. However, the kobs’s
are almost the same (Table 2, entries 2 and 3). Use of aniline
HCl salt instead of triazole HCl salt 7 does not affect the reaction
rate (Table 2, entry 1), which is consistent with previous
observations.. The data are consistent with the rate-determining
step being the formation of the R-oxoketene intermediate 2 under
the one-pot conditions developed for synthetic applications.
Attempts To Directly Observe R-Oxoketene Species. The
decarboxylation step was also studied by using a special IR
probe (Sicomp) in an attempt to detect ketene-related intermedi-
ates. However, in the presence or absence of triazole HCl salt
As shown in Table 3, entries 3 and 4, only minor amounts
of 16 are formed initially, and it grows in as the reaction
proceeds at the expense of 15. Clearly, 16 is formed by
decarboxylation of 15 under the reaction conditions, although
decarboxylation by enolation can be suppressed in the presence
of a strong acid (Table 3, entries 1 and 5). Therefore, formation
of 16 does not provide evidence for a reaction pathway through
a protonated ketene (such as 18 or 19) or ketene intermediate;
in contrast, the fact that the ratio of 16/15 is suppressed to 2:98
in the presence of TFA indicates that formation of 16 is from
direct cyclization of the protonated 17. When reaction of 14 is
carried out in the absence of additional acid (entry 3), 17 could
only arise via protonation by acyl Meldrum’s acid 14 itself,
followed by Friedel-Crafts-type reaction with the electron-rich
7
with various TFA charges, no ketene species could be detected
by online IR. This is not surprising and is consistent with our
kinetic results which showed the decarboxylation to form the
R-oxoketene step is the rate-determining step and there is no
accumulation of R-oxoketene intermediate in the reaction
solution.32
1
4
aromatic ring. It is also possible that unprotonated 14 is
sufficiently reactive such that protonation is not required for
cyclization to occur. To summarize, this intramolecular trapping
+
experiment indicated that protonated intermediate 17 (H A )
2
is a possible intermediate in these reactions, but provided no
evidence for the formation of protonated ketene intermediates
such as 18 and 19.
Model and Bridging Studies. Thus far, the kinetic data
outlined above are consistent with formation of an R-oxoketene
that arises from the free acid form, HA. Although the reaction
is conducted under acidic conditions, the kinetics are consistent
with reaction via the free acid HA, not the protonated acid
+
H2A . To determine if the protonated acyl Meldrum’s adduct
+
H2A and the protonated ketene are viable intermediates under
the conditions used in the process described above, a model
study was designed to trap the intermediates. It has been reported
(
32) Hydration, aminolysis, and alcoholysis of ketenes are fast reactions. In
comparison of the reaction rate constants the self-decomposition of 6 with
reported k for hydration, or aminolysis, or alcoholysis of ketenes, the
reaction rate difference could be up to 10 orders of magnitude. (a) Chiang,
Y.; Guo, H.-X.; Kresge, A. J.; Tee, O. S. J. Am. Chem. Soc. 1996, 118,
Bridging Studies with Other Substrates. Up to now we
have described reactions of Meldrum’s adducts with various
nucleophiles including amines of varying basicity and nucleo-
philicity, alcohols, and carbamates. Reactions with imines have
been reported in the literature, but under conditions quite
3
386-3391. (b) Allen. A. D.; Andaos, J.; Kresge, A. J.; McAllister, M. A.;
Tidwell, T. T. J. Am. Chem. Soc. 1992, 114, 1878-1879.
1
3008 J. AM. CHEM. SOC. VOL. 126, NO. 40, 2004
9

Formation of
â
-Ketoamides/Esters via Meldrum’s Acid Adducts
A R T I C L E S
Scheme 6. Reaction of 6 with Imines
reported in the literature, we conclude that for the same substrate,
decarboxylation of acyl Meldrum’s adducts is likely occurring
through the same reaction pathway.
Conclusion
A practical one-pot process for preparation of â-keto amides
has been developed. Use of online IR and subsequent principal
component analysis for kinetic studies were critical as a tool
for profiling the concentration changes of the anion and free
acid forms, as well as the product, throughout the course of the
reaction. Kinetic mechanistic studies clearly revealed that
formation of â-keto amides from acyl Meldrum’s adducts were
generated via the R-oxoketene intermedate 2 either under
synthetically relevant reaction conditions or in a “clean” system,
in which only isolated acyl Meldrum’s adduct 6 and amine free
base were involved. The formation of R-oxoketene was also
demonstrated by kinetic studies on the self-decomposition of
acyl Meldrum’s adducts under a variety of conditions. The
different from those we developed for the keto-amide formation.
We wanted to determine if the experimental conditions we were
operating under for keto-amide and keto-ester formation could
be bridged to those reported in the literature for reaction with
imines, since different pathways may be involved for the same
substrate under different reaction conditions. We chose the
imines 20, 22, and 24 since they have been reported in previous
studies (Scheme 6).
-
anionic form A was shown to be stable and not directly
involved in nucleophilic addition or self-decomposition, while
the free acid form HA was responsible for generating R-oxo-
ketene intermediate 2. The possibility of protonated R-oxoketene
intermediates involvement in the formation of â-keto amides
was unambiguously ruled out based on the observed kinetic
profiles. Our kinetic studies on acyl Meldrum’s acid 6 with
various substrates (such as carbamates, alcohols, and amines)
and the “bridging” studies on the thiazolines also clearly
demonstrated that R-oxoketene intermediates are the main
reaction pathway. However, if a nucleophile or a substrate is
A mixture of 2 equiv of 6 and 1 equiv of thiazoline 20 was
saturated with HCl(g) and aged in refluxing benzene as
3
described in the literature for preparation of â-lactams. The
29
+
desired â-lactam 21 was isolated in 41% yield. Similarly,
able to react with H2A before it can be converted to an
2
treatment of 6 with the substituted ∆ -thiazoline 22 in HCl(g)-
R-oxoketene intermediate, then the pathway to trap the pro-
saturated 1,2-dichloroethane at 65 °C for 3 h gave the pyridinone
tonated acyl Meldrum’s acids becomes possible and formation
of products such as 15 and 1,3-oxazinones could be observed.
2
9
6
2
3 in 80% yield. The above two reactions were also carried
out in the absence of HCl(g). Although the reaction did not
proceed as cleanly as in the presence of HCl(g), formation of
the â-lactam 21 and pyridinone 23 was clearly observed,
respectively. These control experiments confirmed that HCl(g)
is not necessary to lead to formation of the â-lactam or
pyridinone in both cases.
Supporting Information Available: All kinetic profiles,
experimental procedures, and spectral data of 6 and 8. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA046488B
When 6 was treated with N-benzylidene methylamine (24)
(
33) (a) Piettre A.; Chevenier, E.; Masardier, C.; Gimbert, Y.; Greene, A. Org.
Lett. 2002, 4, 3139-3142. (b) Plazuk, D.; Zakrzewski, J. J. Org. Chem.
2002, 67, 8672-8674.
6
a
in MeCN at 55 °C for 5 h instead of in refluxing benzene, the
expected product 25 was also obtained.34 Since the same
products are generated under either our conditions or those
(34) See ref 6a. Yamamoto et al. confirmed oxazin-4-ones are formed if acyl
Meldrum’s acids are subjected to the same reaction conditions.
J. AM. CHEM. SOC.
9
VOL. 126, NO. 40, 2004 13009