Preparation and chemistry of an unexpectedly stable α-oxoketene-pyridine zwitterion, 2,2-bis(tert-butylcarbonyl)-1-[4-(dimethylamino)pyridinio]ethen-1-olate

Article abstract of DOI:10.1002/1099-0690(200104)2001:7<1315::AID-EJOC1315>3.0.CO;2-2

Treatment of dipivaloylketene 1 and its dimers 2 and 3 with 4-(dimethylamino)pyridine (DMAP) in acetonitrile affords the α-oxoketene-pyridine zwitterion 4 as a pale yellow solid. This is the first example of a stable zwitterion obtained from a true α-oxok

Full text of DOI:10.1002/1099-0690(200104)2001:7<1315::AID-EJOC1315>3.0.CO;2-2

FULL PAPER
Preparation and Chemistry of an Unexpectedly Stable α-Oxoketene؊Pyridine
Zwitterion, 2,2-Bis(tert-butylcarbonyl)-1-[4-(dimethylamino)pyridinio]ethen-
1-olate
Gert Kollenz,*[a] Susanne Holzer,[a] C. Oliver Kappe,[a] Turkaram S. Dalvi,[a]
Walter M. F. Fabian,[a] Heinz Sterk,[a] Ming Wah Wong,[b] and Curt Wentrup[c]
Keywords: Ab initio calculations / Nitrogen heterocycles / Zwitterions
Treatment of dipivaloylketene 1 and its dimers 2 and 3 with
4-(dimethylamino)pyridine (DMAP) in acetonitrile affords
the α-oxoketene-pyridine zwitterion 4 as a pale yellow solid.
This is the first example of a stable zwitterion obtained from
a true α-oxoketene. In anhydrous solution at room temp.,
excellent agreement with the formation and relative stability
of 4. 15N labelling experiments demonstrate that the ring ni-
trogen atom of DMAP is involved in generating the new zwit-
terionic C−N bond. Reactions of 4 with NH and OH nucleo-
philes in solution afforded the corresponding dipivaloyl
compound 4 largely cleaves into the reactants 1 and DMAP. acetic acid derivatives 6 and 7, whereas acetone or benzylid-
At −60 °C the equilibrium is shifted entirely towards the zwit-
terion 4, as shown by 13C NMR measurements. Calculations
using density functional theory (B3LYP/6−311+G**) are in
ene aniline undergo cycloaddition reactions of the hetero-
Diels−Alder type.
Introduction
Ketenes and ketene-nucleophile zwitterions are of con-
tinuing interest from preparative, mechanistic and theoret-
ical points of view.[1] Zwitterionic species have been postu-
lated as reactive intermediates in many reactions,[2] and in
a few cases there is direct experimental evidence for their
existence.[3] The synthesis of β-lactams by keteneϪimine
cycloaddition[2e,4] and the addition of N-nucleophiles to
ketenes[5] have been investigated thoroughly in this context.
It is interesting to note that, in the case of NH nucleophiles,
the corresponding amide enols are formed rapidly, as shown
by 1H and 13C NMR spectroscopy[6] and laser-flash
photolysis with time-resolved infrared spectroscopy.[3i]
Low-temperature matrix isolation has provided direct evid-
ence for the existence and reactivity of keteneϪpyridine
zwitterions.[3g,3h] However, examples of stable keteneϪ
nucleophile zwitterions under normal reaction conditions
are extremely rare.
Dipivaloylketene (1) is generated in nearly quantitative
yield by preparative flash vacuum thermolysis (FVT) of the
corresponding furan-2,3-dione (Scheme 1).[9] Its chemistry
has been well explored.[10] In particular, it slowly dimerizes
at room temp. to afford the extraordinarily stable α-oxoket-
ene 2.[9b] However, when the dimerization is carried out in
the presence of catalytic amounts of pyridine, DMSO, or
phosphanes, among other substances, the dioxinone dimer
3 is obtained instantaneously instead. It was postulated that
a zwitterionic intermediate of type 4 — with pyridine in
place of 4-(dimethylamino)pyridine — was responsible for
the changed mode of reaction.[9b] This proposal was con-
firmed by co-condensing dipivaloylketene (1) with pyridine
vapour at 30 K. Subsequent warming to 100 K caused
formation of the zwitterion, identified by its IR absorption
bands (1677, 1605, 1596 and 1579 cmϪ1). After further
warming to room temperature, the dimer 3 was isolated
(70% yield on a preparative scale).[3g] The electron-donating
effect of the p-dimethylamino group enhances the basicity
of the pyridine nitrogen from pK ϭ 5.22 for pyridine to
9.61 for DMAP. Accordingly, the formation of a more
stable zwitterion could be expected when using DMAP (see
the Theory section).
Gompper and Wolf[3a] were able to isolate and charac-
terise spectroscopically a stable 1:2 zwitterionic adduct (a
secondary product, not a keteneϪpyridine zwitterion) from
the addition of pyridine to bis(ethoxycarbonyl)ketene,[8] as
well as a stable 1:1 adduct from the reaction of the same
ketene with 4-(dimethylamino)pyridine (DMAP).
[a]
Institute of Chemistry, Karl-Franzens University Graz,
Heinrichstrasse 28, 8010 Graz, Austria
Fax: (internat.) ϩ 43-316/380-9840
E-mail: kollenz@kfunigraz.ac.at
[b]
Department of Chemistry, National University of Singapore,
Kent Ridge, Singapore 119260
[c]
Chemistry Department, The University of Queensland,
Brisbane, Qld 4072, Australia
E-mail: wentrup@chemistry.uq.edu.au
Supporting information for this article is available on the
WWW under http://www.wiley-vch.de/home/eurjoc or from
the author.
Here we report the preparation of the stable α-oxoketene
zwitterion 4, obtained by addition of DMAP to the stable
but nonetheless highly reactive dipivaloylketene (1). Altern-
Eur. J. Org. Chem. 2001, 1315Ϫ1322
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1434Ϫ193X/01/0407Ϫ1315 $ 17.50ϩ.50/0
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G. Kollenz et al.
FULL PAPER
Scheme 1
atively, the ketene dimers 2 and 3 can both be used as pre- ine N atom on the ketene. In the preparation of 4 from the
cursors for 4 (Scheme 1).
dimers 2 or 3, a [2ϩ4] cycloreversion is required. This may
be initiated by attack of DMAP on the dimers, thereby
cleaving them to one molecule of keteneϪDMAP zwitter-
ion and one molecule of the monomeric dipivaloylketene.
Results and Discussion
The elemental analysis of 4 confirms the molecular for-
mula of a 1:1 adduct of ketene 1 and DMAP. A FAB mass
spectrum of 4 in a glycerine matrix did not yield a parent
peak. Instead, peaks at m/z ϭ 123 (100%) and 211 (30%)
indicated the presence of the two fragments, DMAP and 1.
A FAB spectrum in a p-nitrobenzyl alcohol (NOBA) matrix
yielded the same two fragments plus a signal at m/z ϭ 486
(10%) corresponding to 4 ϩ NOBA ϩ Hϩ, thus providing
indirect evidence for the presence of the intact molecules 4.
When freshly prepared dipivaloylketene[9b] (1) was added
dropwise to a solution of DMAP (molar ratio 1:1) in dry
acetonitrile at room temperature, a pale yellow precipitate
was formed immediately. After stirring for 20 min the pre-
cipitate (yield 86%) was separated by rapid suction filtration
through a dry sintered glass filter. The adduct is highly
sensitive to moisture, but can be stored in an evacuated de-
siccator over P4O10 for several weeks without degradation.
Starting from the ketene dimers 2 or 3 (molar ratio now
2:1), a similar experimental procedure can be employed.
The IR spectrum of 4 in KBr exhibits absorptions at
After addition of the corresponding dimer as a solid, the 2980Ϫ2850m (tBu), 1660s, 1635s, 1605vs, 1540m and
product precipitated from the clear yellow solutions after 1520m cmϪ1. The bands at 1660 and 1605 cmϪ1 are similar
2Ϫ5 min stirring at room temperature, in yields of 77Ϫ85%. to those of the dipivaloylketeneϪpyridine zwitterion in a
The formation of zwitterion 4 from 1 and DMAP is eas- low temperature matrix (1677, 1605 cmϪ1).[3h] The IR spec-
ily understood as a simple addition of the nucleophile to trum of an equimolar mixture of DMAP and dipivaloylme-
the ketene system. It is interesting to note that, when the thane is very similar to that of the zwitterion, except that
primary amine 4-aminopyridine is employed instead of the bands at 1660Ϫ1635 cmϪ1 are missing, thus indicating
DMAP, the product obtained corresponds to addition of that they are due to the zwitterion. The calculated values
the NH2 group to the ketene function (see below), but this are 1678, 1633, 1611, 1585 and 1541 cmϪ1 (B3LYP/6Ϫ31G*,
product formation may well be preceded by a pre-equilib- ε ϭ 40; see Table S1 in the Supporting Information). In
rium involving the zwitterion formed by attack of the pyrid- contrast, the IR spectrum of 4 in CH2Cl2 solution demon-
1316
Eur. J. Org. Chem. 2001, 1315Ϫ1322

Preparation and Chemistry of an Unexpectedly Stable α-OxoketeneϪPyridine Zwitterion
FULL PAPER
strates the presence of a ketene moiety (2115 cmϪ1) as well
as the CϭO bands. Therefore, in solution, the zwitterion
must exist in equilibrium with the starting components
(vide infra). Further absorptions are at 1662, 1653, 1645
and 1601 (s) cmϪ1
.
1
The H NMR spectrum of compound 4 in dry CDCl3
solution corroborates the dissociation of 4 to the compon-
ents. A singlet at δ ϭ 1.23 (18 H) is due to the tert-butyl
groups of ketene 1. Doublets at δ ϭ 8.22 and 6.50 (2 H
each) together with a singlet at δ ϭ 3.03 (6 H) confirm the
presence of free DMAP. For comparison, virtually identical
chemical shift values of DMAP were recorded for a 1:1 mix-
ture of dipivaloylmethane and DMAP.
Figure 1. Calculated (GIAO-B3LYP/6Ϫ31G*) and observed
(CH2Cl2, Ϫ60 °C) 13C NMR chemical shifts for zwitterion 4; calcu-
lated values are in bold
Similar results were also obtained from numerous 13C
NMR spectra of 4 at significantly higher concentrations
and with CD2Cl2 or CDCl3 as solvents. Here it is extremely
important to perform the whole procedure under thor-
oughly anhydrous conditions. The NMR measurements
themselves must be carried out in sealed tubes in order to
avoid any trace of moisture. Rapid measurements (30 min.)
and long reaction times (overnight) at room temp. allowed
observation of the most intense signals only. The DMAP
carbon atoms C-3,5 (δ ϭ 106.5), C-4 (δ ϭ 156.5) and the
CH3 carbons (δ ϭ 39.5) correlated well with those of several
positively charged (protonated) DMAP species reported in
the literature,[11] as well as unprotonated DMAP itself. In
contrast, the signal for C-2 (C-6) of DMAP was shifted
upfield by 4.7Ϫ5 ppm (!), thereby suggesting the presence
of a fast equilibrium. Because of the rapid exchange, the
chemical shift values found (δ ϭ 144.1Ϫ144.8) represent
signals originating from the mixture of starting materials
and product, giving an approximately 50:50 distribution [C-
butyl group must get close to the pyridine nucleus thus re-
sulting in different shielding/deshielding of the carbons in-
volved. These signals collapsed to singlets again upon
warming and the complete signal pattern of the original
spectrum of the equilibrium at room temp. reappeared.
After addition of D2O, further measurements indicated
rapid hydrolysis to DMAP, as made evident by its most
intense signals at δ ϭ 149.1 and 106.6.
In order to demonstrate that it is the ring nitrogen atom
of the DMAP that attacks the electrophilic carbon atom of
the ketene, 15N-labelling experiments were performed
(Scheme 2). [15N]DMAP, labelled at the ring nitrogen, was
prepared from [15N]pyridine (degree of labelling 20%) via
the 4-pyridylpyridinium chloride (5) (Scheme 2).[12,13]
2/C-6 in free DMAP: δ ϭ 149.8; in protonated DMAP[11]
:
δ ϭ 139.0Ϫ131.0, depending on the specific salt; in 4 at Ϫ
60 °C: δ ϭ 139.5, see also Figure 1]. The carbons vicinal to
the positively charged pyridinium nitrogen usually exhibit
significant upfield shifts.[11] Observation of the carbons of
the ketene scaffold in 4 was difficult at room temp.: the
pivaloyl CϭO was detected at δ ϭ 202.9Ϫ203.5 as a rather
broad signal of low intensity, again representing an average
value of the free dipivaloylketene (δ ϭ 198.9 at Ϫ50 °C[9a]
)
and the zwitterionic species (δ ϭ 211.5 at Ϫ60 °C, see be-
low); signals for the carbon atoms of the ketene function
(CϭCϭO at δ ϭ 52.1 and 194.0) were not found at all. A
priori, these are of low intensity and are probably further
broadened due to the fast equilibrium, since these two car-
bons are most affected upon formation of the zwitterion.
In order to slow down the exchange rate and to shift the
Scheme 2
In the 15N NMR spectrum of [15N]DMAP at room
position of the equilibrium itself towards the adduct, low temp., the chemical shift of the ring nitrogen appears at δ ϭ
temperature experiments were performed. In fact, at Ϫ60 112.5 (relative to nitromethane), while the corresponding
°C (CD2Cl2) a complete assignment of the signals resulting signal for [15N]4 is shifted to δ ϭ 121.0. Usually, ring nitro-
from the zwitterion was possible (Figure 1). No signals due gens of pyridinium compounds exhibit signals some
to free DMAP itself were detectable, thus indicating that 50Ϫ100 ppm downfield from their neutral analogues.[14]
the equilibrium had shifted entirely towards the zwitterion. For example, the ring nitrogens of closely related pyridin-
In addition, because of hindered rotations of the pivaloyl ium dicyanomethylides appear in the range
δ
ϭ
moieties, the signals of the pyridinium nucleus split into 150Ϫ170.[15] The small downfield shift in [15N]4, together
doublets at temperatures of Ϫ40 °C and below since, as with a broadening of the signal at δ ϭ 121.0, again support
easily deduced from models, either the carbonyl or the tert- the existence at room temp. of the equilibrium outlined in
Eur. J. Org. Chem. 2001, 1315Ϫ1322
1317

G. Kollenz et al.
FULL PAPER
Scheme 1. Because of a high rate of exchange, the signal carried out using the Gaussian 98 series of programs.[19]
represents an average value between that of free DMAP and Full geometry optimizations were performed with the
the DMAPϪketene adduct, with the equilibrium strongly B3LYP method,[20] using the split-valence polarized
shifted toward the starting materials, DMAP and dipiva- 6Ϫ31G* basis set. Higher-level relative energies were ob-
loylketene (perhaps by 80Ϫ90%). This experiment also con- tained through B3LYP/6Ϫ311ϩG** calculations, including
firms that DMAP attacks the ketene through the ring nitro- a zero-point vibrational correction. The effect of a dielectric
gen atom. In a quite different area of investigation, it was medium was examined using Onsager’s self-consistent-reac-
concluded that the catalytic activity of DMAP in rearrange- tion field theory.[21] NMR chemical shift calculations were
ments of thionocarbonates is also due to ring nitrogen at- performed using the gauge-independent atomic orbital
tack.[16]
(GIAO) method.[22] Infrared spectra were computed at the
B3LYP/6Ϫ31G* level and the calculated frequencies were
scaled by a factor of 0.9613.[23]
Chemistry of 4
The zwitterionic structure 4 is calculated to be a stable
species in the gas phase. It is characterized by a rather
short, ylide-type CϪN bond length of 1.558 A (Figure 2).
It is well documented that dipivaloylketene 1 adds prim-
ary amines to give the corresponding dipivaloylacetami-
des.[10b] In view of the equilibrium between zwitterion 4 and
the starting materials, it is not surprising, therefore, that 4
reacted with primary amines to afford amides 6 in moderate
to good yields. Nevertheless, ketene reactions are known to
be catalysed by pyridines and other amines;[1b] hence it is
not necessarily the monomeric ketene 1 itself that is re-
acting. Similarly, with alcohols, the corresponding dipiva-
loyl acetates 7 were obtained in yields of 60Ϫ80%. Remark-
ably, compounds 6 and 7 (Scheme 3) did not show any tend-
ency to enolize in CDCl3 solution, although enols should
be stabilized by intramolecular hydrogen bonds. Earlier ex-
perimental and theoretical investigations into the keto-enol
tautomerism of β-tricarbonyl compounds demonstrated in-
fluences arising from the physical condition of the sample
as well as the kind of solvent employed.[17]
˚
For comparison, the parent keteneϪpyridine (CH2CO/
C5H5N) analogue is predicted to be a weak van der Waals
˚
complex with a long CϪN distance of 2.073 A. This, to-
gether with other calculations we have performed, indicates
that ketene-pyridine ylides are stabilized by electron-with-
drawing substituents on the ketene and electron-donating
substituents on the pyridine. The zwitterion 4 has a very
large dipole moment of 14.4 Debyes. Based on natural bond
orbital (NBO)[24] analysis at B3LYP/6Ϫ31G*, 4 is calcu-
lated to have a large degree of charge transfer (0.56 e) from
DMAP to dipivaloylketene. Significant charge alternation
is also seen in the charge distribution of 4 (Figure 3). In
the presence of a polar medium (ε ϭ 40), the zwitterion is
significantly stabilized: the CϪN bond length is shortened
˚
by 0.038 A, while the charge transfer is increased by 0.07 e.
Because of steric repulsion, the ketene and pyridine subun-
its of 4 are not coplanar (τCCNC ϭ 40°). It is interesting
to note that the CH···O interaction also plays an important
role in stabilizing this complex. The distance between the
˚
ketene oxygen and the pyridine ortho-hydrogen is 2.373 A,
significantly shorter than the sum of their van der Waals
˚
radii (3.05 A). Likewise, the distance between the carbonyl
˚
oxygen and the ortho-hydrogen is relatively short (2.889 A).
Scheme 3
The ortho-CϪH stretch is blue shifted to a higher wave-
number (by 85 cmϪ1) on going from the monomer (DMAP)
to the zwitterion 4. A similar CH···O interaction has been
Dipivaloylketene 1 serves as an excellent oxadiene system
in [4 ϩ 2] cycloaddition reactions with CϭO, CϭN and
CϭS dienophiles.[18] In order to examine the ability of the
zwitterion 4 to undergo similar reactions, dry acetone and
benzylideneaniline were selected as dienophiles. The corres-
ponding cycloadducts, 1,3-dioxin-4-one and 1,3-oxazin-4-
one derivatives 8 and 9 (Scheme 4), were obtained in yields
of 81% and 76%, respectively.
[25]
observed for the C3O2···pyridine complex.
How stable is the zwitterion? The calculated enthalpy of
formation of 4 is endergonic in the gas phase (∆G298
ϭ
20 kJ molϪ1, Table 1), but a polar medium has a strong
influence on the stability of this polar species. In a nonpolar
environment (ε ϭ 2), the formation of the zwitterion is
slightly preferred (∆G298 ϭ Ϫ6 kJ molϪ1). This is in good
accord with the experimental observation that 4 is in equi-
librium with DMAP ϩ 1 in CH2Cl2 solvent. In a polar
medium of ε ϭ 40, the equilibrium is strongly shifted to-
wards the zwitterion (∆G298 ϭ Ϫ24 kJ molϪ1). Dissociation
of 4 to dipivaloylketene (1) and DMAP is predicted to have
a small activation barrier of 4 kJ molϪ1. However, this bar-
rier increases substantially to 34 kJ molϪ1 in a dielectric
medium of ε ϭ 40. As seen in Figure 1, the calculated 13C
Scheme 4
Theory
To determine the structure and stability of the ketene- NMR chemical shifts (B3LYP/6Ϫ31G*) are in excellent ac-
pyridine zwitterion 4, density functional calculations were cord with the experimental data. Likewise, the calculated
1318
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Preparation and Chemistry of an Unexpectedly Stable α-OxoketeneϪPyridine Zwitterion
FULL PAPER
˚
Figure 2. Optimized (B3LYP/6Ϫ31G*) structural parameters (bond lengths in A and angles in degrees) of 4 in the gas phase (upright
numbers) and in a polar medium of ε ϭ 40 (numbers in italics)
Figure 3. Calculated NBO atomic charges of 4 in the gas phase; the corresponding values in the precursors 1 and DMAP are given
in italics
infrared frequencies agree well with the observed values
(Table S1). In summary, calculation strongly supports the
Conclusion
characterization of zwitterion 4.
Zwitterion 4, obtained from treatment of dipivaloylket-
ene (1) or its dimers 2 or 3 with 4-(dimethylamino)pyridine,
is remarkably stable in the solid state (m.p. Ͼ170 °C!). It
represents the first example of a stable zwitterion of this
kind derived from a true α-oxoketene. In completely anhyd-
rous solution (such as CD2Cl2, CDCl3) the adduct dissoci-
ates into the reactants, thus creating a fast equilibrium at
room temp. At low temperature (Ϫ60 °C), the equilibrium
is shifted nearly completely towards the zwitterionic adduct,
as evidenced by 13C NMR measurements. This can be at-
tributed to a negative ∆S° for zwitterion formation. The
adduct 4 is highly sensitive to moisture, immediately hydro-
lysing into 4-(dimethylamino)pyridine and dipivaloylme-
thane. The stability and properties of 4 are in excellent ac-
cord with density functional quantum chemical calcula-
Table 1. Calculated energies of 4 (kJ molϪ1
)
Enthalpy/free energy of formation[a][b]
Barrier
ε ϭ 1
ε ϭ 2
ε ϭ 40
ε ϭ 1 ε ϭ 2 ε ϭ 40
∆H0
∆H298
∆G298
6.9
4.9
20.0
Ϫ18.5
Ϫ20.6
Ϫ5.7
Ϫ37.1
Ϫ39.3
Ϫ24.1
3.5 15.9 37.4
4.8 15.1 36.7
3.7 14.0 35.7
[a]
B3LYP/6Ϫ311ϩG**//B3LYP/6Ϫ31G* ϩ ZPVE level. Calcu-
lated total energies (ε ϭ 1) for 1, DMAP, 4 and T.S. are
Ϫ693.76630, Ϫ382.25730, Ϫ1076.03291 and Ϫ1076.02659 Har-
trees, respectively. Calculated zero-point vibrational energies (ε ϭ
1) for 1, DMAP, 4 and T.S. are 724.6, 420.4, 1156.7 and 1150.9 kJ
molϪ1, respectively. Ϫ [b] The free energies were calculated using the
formula ∆G ϭ ∆H Ϫ T∆S. Calculated entropies (S) for 1, DMAP, 4
and T.S. were 134.5, 89.9, 173.0 and 176.7 J molϪ1KϪ1, respectively. tions. Reactions between 4 and nucleophiles, as well as its
Eur. J. Org. Chem. 2001, 1315Ϫ1322
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G. Kollenz et al.
FULL PAPER
brownish residue was triturated with dry ethanol (1 mL) to afford a
suspension, which was centrifuged (3000 rpm) for 3 min. The liquid
layer was removed and the residue was transferred into a round
bottomed flask with the aid of 2 mL of dry ethanol. The ethanol
was evaporated to afford brownish crude 5 (900 mg).
cycloaddition reactions, reveal chemical behaviour identical
with that of dipivaloylketene 1 itself.
Experimental Section
(b) 4-(Dimethylamino)[15N]pyridine:[12,13] Crude 5 (900 mg) was re-
fluxed in freshly distilled dimethylformamide (1.5 mL) for 2 h (bath
temperature 180 °C). After cooling, aqueous sodium hydroxide
(3.6 mL, 1% solution) was added to the dark suspension, which
was stirred for 1 h at 20 °C. The reaction mixture was subsequently
extracted five times, each with 6.0 mL of dichloromethane, and
checked by TLC. The combined organic layers were dried over
Na2SO4, decolourised by short boiling with charcoal, and evapor-
ated. The pale yellow residue was recrystallized from diisopropyl
ether and dried by lyophilization to afford pure 4-(dimethylami-
no)[15N]pyridine (90 mg, 6% based on pyridine). 15N NMR
(CDCl3): δ ϭ 112.5 (referenced to nitromethane).
General: 5-tert-Butyl-4-pivaloyl-2,3-dihydrofuran-2,3-dione and di-
pivaloylketene 1 and its dimers 2 and 3 were prepared according
to the literature.[9b] [15N]pyridine (95% 15N) was purchased from
Chemotrade (Germany). All commercial materials were used with-
out further purification. Liquids and solvents, including NMR
solvents (CD2Cl2, CDCl3), were dried over molecular sieves
(Merck, 0.4 nm); n-hexane was freshly distilled before use; solid
materials were stored over P4O10. All reactions were performed un-
der dry N2, and the reaction vessels were equipped with CaCl2
tubes. Ϫ 1H, 13C and 15N NMR spectra were recorded on a Varian
X-200 (Gemini Version) and/or a Bruker 360 MHz instrument (se-
lected 13C NMR spectra are available as Supporting Information).
Ϫ IR spectra were recorded on a PerkinϪElmer 298 spectrometer
and UNICAM Galaxy Series 7000 (FTIR). Ϫ Mass spectral data
(FAB mode) were obtained on a VG ZAB-2SEQ, MS-902 spectro-
meter.
(c) [15N]4: Dimer 3 (100 mg, 0.23 mmol) was added to 4-(dimethyl-
amino)[15N]pyridine (70 mg, 0.45 mmol, degree of labelling 19%)
dissolved in dry acetonitrile (0.5 mL). After 3 min. stirring at 20
°C, a yellow solid started to precipitate. After 30 min. this was
separated by suction filtration and immediately stored over P4O10
in an evacuated desiccator. Yield 90 mg (52%). Ϫ 15N NMR
(CDCl3): δ ϭ 121 (reference to nitromethane).
Synthesis of 2,2-Bis(tert-butylcarbonyl)-1-[4-(dimethylamino)pyridi-
nio]ethen-1-olate (4). ؊ (a) From Dipivaloylketene (1): Dipivaloylke-
tene (1) (300 mg, 1.43 mmol), freshly prepared by flash vacuum
thermolysis of the corresponding furandione,[9b] was rapidly added
dropwise with stirring to a solution of 4-(dimethylamino)pyridine
(‘‘Steglich’’ base, 180 mg, 1.48 mmol) in dry acetonitrile (2.5 mL).
During this procedure a yellow solid started to precipitate, and the
resulting reaction mixture was stirred for 20 min. at 20 °C. The
yellow precipitate was separated by rapid suction filtration and im-
mediately stored in an evacuated desiccator over P4O10 (yield
407 mg, 86%), m.p. Ͼ170 °C (closed capillary). Ϫ 1H NMR
(200 MHz, CDCl3; the spectrum is the result of dissociation into 1
and DMAP): δ ϭ 1.23 (s, 18 H, tBu), 3.03 (s, 6 H, CH3), 6.50 (d,
J ϭ 8.5 Hz, 2 H), 8.22 (d, J ϭ 8.5 Hz, 2 H). Ϫ 13C NMR
(90.5 MHz, CD2Cl2, Ϫ60 °C): see Figure 1. Ϫ IR (KBr): ν˜ ϭ
3020Ϫ2860, 1650, 1605 cmϪ1. Ϫ FT-IR (CD2Cl2): ν˜ ϭ 2969, 2115,
1662, 1653, 1645, 1638, 1601 cmϪ1. Ϫ FAB-MS: (a) glycerine mat-
rix m/z (%) ϭ 57 (90) [tBu], 123 (100) [M ϩ 1, DMAP], 211 (30)
[M ϩ 1, 1]; (b) p-nitrobenzyl alcohol matrix m/z (%) ϭ 57 (40)
[tBu], 123 (100) [M ϩ 1, DMAP], 211 (10) [M ϩ 1, 1], 486 (10) [4
ϩ NOBA ϩ 1]. Ϫ C19H28N2O3 (332.44): calcd. C 68.64, H 8.49, N
8.34; found C 68.88, H 8.89, N 8.49.
Reactions between Zwitterion 4 and Primary Amines. ؊ N-(4-Pyri-
dyl)dipivaloylacetamide (6a). ؊ (a) From 4: Solid 4-aminopyridine
(30 mg, 0.3 mmol) was added to
a solution of 4 (100 mg,
0.45 mmol) in DMF (1.5 mL). The solution decolourised and was
stirred at 20 °C for 20 min. After addition of diethyl ether (3 mL),
it was washed with 0.35 mL of aqueous HCl (1 ). The organic
layer was dried over sodium sulfate and evaporated. The crude
amide was recrystallized from n-hexane to afford 60 mg of 6a
(55%). Ϫ b) From 1: Dipivaloylketene (1) (210 mg, 1.0 mmol) was
added dropwise to
a solution of 4-aminopyridine (94 mg,
1.0 mmol) with stirring. After 1 h at 20 °C, the solvent was evapor-
ated and the remaining crude product was recrystallized from n-
hexane to give 235 mg (78%) of colourless crystals, m.p. 165Ϫ166
°C. Ϫ IR (KBr): ν˜ ϭ 3140, 3000Ϫ2860, 1715, 1690, 1600 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 1.22 (s, 18 H, tBu), 5.81 (s, 1 H, CH), 7.44
(d, J ϭ 9.0 Hz, 2 H), 8.48 (d, J ϭ 9.0 Hz, 2 H), 8.90 (br s, 1 H, NH).
Ϫ C17H24N2O3 (304.39): calcd. C 67.08, H 7.95, N 9.20; found C
67.02, H 8.01, N 9.27.
N-(4-Tolyldipivaloyl)acetamide
(6b):
p-Toluidine
(60 mg,
0.56 mmol) dissolved in dry acetonitrile (1.5 mL) was added drop-
wise to a solution of 4 (150 mg, 0.45 mmol) in dry acetonitrile
(5 mL). After 20 min. stirring at 20 °C, the yellow solution decol-
ourised, and the acetonitrile was removed in vacuo. Trituration
with 3 mL of n-hexane dissolved the 4-(dimethylamino)pyridine
and the remaining colourless residue was recrystallized from n-hex-
ane to yield 90 mg (63%) of 6b; m.p. 126 °C. Ϫ IR(KBr): ν˜ ϭ 3300,
2970, 1725, 1700, 1605 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.27 (s,
18 H, tBu), 2.32 (s, 3 H, CH3), 5.79 (s, 1 H, CH), 7.12 (d, J ϭ
9.5 Hz, 2 H), 7.39 (d, J ϭ 9.5 Hz, 2 H), 8.61 (br s, 1 H, NH). Ϫ
C19H27NO3 (317.43): calcd. C 71.89, H 8.57, N 4.41; found C
71.36, H 8.72, N 4.28.
(b) From Dimer 2: Solid 2 (300 mg, 0.71 mmol) was added to a
solution of 4-(dimethylamino)pyridine (180 mg, 1.48 mmol) in dry
acetonitrile (2.5 mL). The solution turned yellow, and after 2Ϫ3
min. the yellow product (365 mg, 77%) precipitated. The reaction
mixture was stirred for another 30 min at 20 °C. The final workup
was performed as described under (a).
(c) From Dimer 3: Compound 4 (140 mg, 89%) was obtained by
exactly following the procedure given under (b), from 4-(dimethyl-
amino)pyridine (60 mg, 0.49 mmol) and dimer
0.24 mmol) in dry acetonitrile (1.0 mL).
3 (100 mg,
Synthesis of [15N]4. (a) 4-[15N]Pyridyl-[15N]pyridinium Chloride
(5):[12,13] Thionyl chloride (2.0 mL, 27.5 mmol) was added dropwise
to a mixture of [15N]pyridine (200 mg, degree of labelling 95%) and
dry pyridine (0.8 mL, 12.7 mmol, degree of labelling now 19.3%).
N-(Benzyldipivaloyl)acetamide (6c): Freshly distilled benzylamine
(50 mg, 0.46 mmol), dissolved in dry acetonitrile (2.0 mL), was
rapidly added dropwise to a solution of 4 (150 mg, 0.45 mmol) in
The solution was allowed to stand at 20 °C for 6 days, forming a dry acetonitrile (4 mL). After stirring for 1 h at 20 °C and evapora-
deep brownish, viscous liquid. The excess of thionyl chloride was
tion of the solvent, the residue was dissolved in 200µL of ethyl
acetate. This solution was filtered through a short column (3.5 g of
removed at the vacuum line (10Ϫ3 mbar) by lyophilization and the
1320
Eur. J. Org. Chem. 2001, 1315Ϫ1322

Preparation and Chemistry of an Unexpectedly Stable α-OxoketeneϪPyridine Zwitterion
FULL PAPER
Merck 60 H silica gel) using 30 mL of ethyl acetate/petroleum ether
(3:5) as eluent. The combined filtrates were again filtered through
a fine-pore sintered glass filter and evaporated. The crude product
was recrystallized from n-hexane to obtain 117 mg (82%) of colour-
less crystals, m.p. 130Ϫ132 °C. Ϫ IR(KBr): ν˜ ϭ 3350, 3000Ϫ2860,
76.75, H 7.51, N 3.44. The spectroscopic data were identical with
those presented in ref.[18]
Acknowledgments
This research was supported by the Karl Franzens University of
Graz, The National University of Singapore (computer time) and
the Australian Research Council.
1
1720, 1705, 1655 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.22 (s, 18 H,
tBu), 4.40 (d, J ϭ 5.0 Hz, 2 H), 5.75 (s,1 H, CH), 7.12 (br s, 1 H,
NH), 7.20Ϫ7.33 (m, 5 H). Ϫ C19H27NO3 (317.43): calcd. C 71.89,
H 8.57, N 4.41; found C 71.80, H 8.49, N 4.53.
[1] [1a]
H. Staudinger, Die Ketene, Verlag F. Enke, Stuttgart, 1912,
p 70Ϫ88. Ϫ [1b] T. T. Tidwell, Ketenes; John Wiley & Sons, Inc.,
New York, 1995, particularly chapters 3.5 and 5.5. Ϫ
N-Cyclohexyl-dipivaloylacetamide (6d): Freshly distilled cyclohexyl-
amine (20 mg, 0.30 mmol), dissolved in dichloromethane (100 µL),
was mixed with 4 (60 mg, 0.30 mmol), dissolved in dichlorome-
thane (1.5 mL), and stirred at 20 °C for 1 h. The decolourised solu-
tion was evaporated, and the residue was treated with diethyl ether
(3 mL) and washed with aqueous 1  HCl (0.3 mL) to remove the
4-(dimethylamino)pyridine. The organic layer was evaporated and
the crude residue recrystallized from n-hexane to afford 90 mg
(54%) of pure 6d, m.p. 116Ϫ118 °C. Ϫ IR (KBr): ν˜ ϭ 3380Ϫ3300,
[1c]
E.
Schaumann, S. Scheiblich, in Methoden der Organischen
Chemie (Houben-Weyl); Thieme-Verlag, Stuttgart, 1993; Vol.
E15, Part 2, p.2479Ϫ2489. Ϫ [1d] C. Wentrup, W. Heilmayer, G.
Kollenz, Synthesis 1994, 1219Ϫ1248.
[2]
[2a]A. Medici, G. Fantin, M. Fogagnolo, P. Pderini, A. Don-
doni, G. D. Andreetti, J. Org. Chem. 1984, 49, 590Ϫ596.[2b] H.
W. Moore, W. G. Duncan, J. Org. Chem. 1973, 38, 156Ϫ158.
[2c]
Ϫ
S. A. Procter, G. A. Taylor, J. Chem. Soc. 1965,
5877Ϫ5880.[2d] E. Schaumann, S. Grabley, M. Henriet, L. Gho-
1
3000Ϫ2860, 1720, 1640 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.1Ϫ2.0
sez, R. Touillaux, J. P. Declercq, G. Germain, M. Van Meer-
sche, J. Org. Chem. 1980, 45, 2951Ϫ2955.[2e] W. T. Brady, C. H.
(m, 28 H, CH2 and tBu), 3.65 (m, 1 H), 5.64 (s, 1 H, CH), 7.27 (br
s., 1 H, NH). Ϫ C18H31NO3 (309.45): calcd. C 69.87, H 10.10, N
4.53; found C 69.99, H 10.17, N 4.50.
[2f]
Shieh, J. Org. Chem. 1983, 48, 2499Ϫ2502. Ϫ
S. Mitkidou,
S. Papadopoulos, J. Stephanidou-Stephanatou, A. Terzis, D.
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J. Jähme, C. Rüchardt, Angew. Chem. Int. Ed. Engl. 1981, 20,
885Ϫ886.
Reactions of Zwitterion 4 with Alcohols. ؊ General Procedure: The
alcohol (0.35 mmol) was injected into a solution of 4 (110 mg,
0.33 mmol) in dichloromethane (4.0 mL), causing immediate decol-
ourisation of the reaction mixture. After stirring for 2 h at 20 °C
the solvent was partially evaporated to approximately 25% of its
original volume, and diethyl ether (3 mL) was added. Extraction
with 0.35 mL aqueous HCl (1 ) removed the 4-(dimethylamino)-
pyridine. The organic layer was pipetted off and the aqueous solu-
tion again extracted twice with ether (2 ϫ 1 mL). The combined
ether solutions were dried over sodium sulfate. Careful evaporation
of the ether at 20 °C afforded the crude products, which could be
recrystallized from n-hexane and should be stored under a dry at-
mosphere.
[3] [3a]
R. Gompper, U. Wolf, Liebigs Ann. Chem. 1979,
[3b]
1388Ϫ1405. Ϫ
Schwarz, J. Org. Chem. 1982, 47, 2233Ϫ2234. Ϫ
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J. Pacansky, J. S. Chang, D. W. Brown, W.
[3c]
E. D. Ed-
[3d]
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M. Barra, T. A. Fisher, G. J. Cernigliaro, R. Sinta, J. C.
[3e]
Scaiano, J. Am. Chem. Soc. 1992, 114, 2630Ϫ2634. Ϫ
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Chelain, R. Goumont, L. Hamon, A. Parlier, M. Rudler, H.
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8088Ϫ8098.[3f] B. Chantegrey, C. Deshayes, R. Faure, Tetrahed-
[3g]
ron Lett. 1995, 36, 7859Ϫ7862. Ϫ
G. Qiao, J. Andraos, C.
Wentrup, J. Am. Chem. Soc. 1996, 118, 5634Ϫ5638.[3h] P.
Visser, R. Zuhse, M. W. Wong, C. Wentrup, J. Am. Chem. Soc.
1996, 118, 12598Ϫ12602. Ϫ [3i] B. D. Wagner, B. R. Arnold, G.
S. Brown, J. Lusztyk, J. Am. Chem. Soc. 1998, 120, 1827Ϫ1834.
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H. W. Moore, G. Hughes, K. Srinivasachar, M. Fernandez,
N. V. Nguyen, D. Schoon, A. Tranne, J. Org. Chem. 1985, 50,
Methyl Dipivaloylacetate (7a): M.p. 49Ϫ50 °C; for analytical and
[4b]
4231Ϫ4238. Ϫ
L. S. Hegedus, J. Montgomery, Y. Naru-
[9a]
[10b]
spectroscopic data see ref.
and
.
kawa, D. C. Snustad, J. Am. Chem. Soc. 1991, 113, 5784Ϫ5791.
[4c]
Ϫ
J. A. Sordo, J. Gonzalez, T. L. Sordo, J. Am. Chem. Soc.
[4d]
Ethyl Dipivaloylacetate (7b): M.p. 59Ϫ61 °C; for analytical and
1992, 114, 6249Ϫ6251. Ϫ
D. C. Fang, X. Y. Fu, THEO-
[9a]
[10b]
CHEM 1998, 455, 59Ϫ68.
J. Andraos, A. J. Kresge, J. Am. Chem. Soc. 1992, 114,
5643Ϫ5646.
spectroscopic data see ref.
and
.
[5]
tert-Butyl Dipivaloylacetate (7c): M.p. 76Ϫ78 °C. Ϫ IR (KBr): ν˜ ϭ
3240, 3020Ϫ2800, 1710, 1685, 1600 cmϪ1. Ϫ 1H NMR (CDCl3):
δ ϭ 1.20 (s, 18 H, tBu), 1.49 (s, 9 H, tBu), 5.77 (s, 1 H, CH).
Ϫ C16H28O4 (284.3932): calcd. C 67.57, H 9.92; found C 67.65,
H 10.01.
[6]
[7]
J. Frey, Z. Rapoport, J. Am. Chem. Soc. 1996, 118, 3994Ϫ3995.
T. T. Tidwell, Ketenes, John Wiley & Sons, Inc., New York,
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H. Staudinger, H. Hirzel, Ber. Dtsch. Chem. Ges. 1917, 49,
[8b]
2522Ϫ2529. Ϫ
S. M. Newman, E. A. Zuech, J. Org. Chem.
1962, 27, 1436Ϫ1439. Ϫ [8c] R. Leung-Toung, C. Wentrup, Tet-
rahedron 1992, 48, 7641Ϫ7654.[8d] S. Nakanishi, K. Butler, Org.
6-tert-Butyl-2,2-dimethyl-5-pivaloyl-1,3-dioxin-4-one (8): Dry acet-
one (22 µL, 0.3 mmol) was injected with the aid of a syringe into
a solution of 4 (100 mg, 0.3 mmol) in dichloromethane (3.0 mL).
The solution decolourised slowly and after stirring for 3 h at 20 °C
the solvent was evaporated to a volume of approximately 1 mL.
Diethyl ether (3 mL) was added, and the further workup followed
the procedure described for the preparation of compounds 7. Yield
65 mg (81%), m.p. 56Ϫ58 °C. Ϫ C15H24O4 (268.35): calcd. C 67.14,
H 9.01; found C 66.93, H 9.07. The spectroscopic data exactly
match those reported in ref.[18]
[8e]
Prep. Proc. Int. 1975, 7, 155Ϫ158. Ϫ
K. T. Potts, M.
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C. O. Kappe, R. Evans, C. H. L. Kennard, C. Wentrup, J.
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A. R. Katritzky, M. S. Chauder Rao, J. Stevens, J. Hetero-
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(9): Compound 4 (100 mg, 0.3 mmol) was treated with benzylidene-
aniline (55 mg, 0.3 mmol) exactly following the experimental pro-
cedure described for 8. Yield 90 mg (76%); m.p. 160Ϫ162 °C. Ϫ
C25H29NO3 (391.51): calcd. C 76.70, H 7.47, N 3.58; found C
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Eur. J. Org. Chem. 2001, 1315Ϫ1322
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[O00483]
1322
Eur. J. Org. Chem. 2001, 1315Ϫ1322