Alkoxyallene-Based LANCA Three-Component Synthesis of 1,2-Diketones, Quinoxalines, and Unique Isoindenone Dimers and a Computational Study of the Isoindenone Dimerization

Article abstract of DOI:10.1002/ejoc.202000116

A series of β-alkoxy-β-ketoenamides was prepared by the well-established LANCA three-component reaction of lithiated 1-(2-trimethylsilylethoxy)-substituted allenes, nitriles, and α,β-unsaturated carboxylic acids. The α-tert-butyl-substituted compounds were smoothly converted into the expected 1,2-diketones by treatment with trifluoroacetic acid. A subsequent condensation of the 1,2-diketones with o-phenylenediamine provided the desired highly substituted quinoxalines in good overall yield. Surprisingly, the α-phenyl-substituted β-alkoxy-β-ketoenamides investigated afford not only the expected 1,2-diketones, but also pentacyclic compounds with an anti-tricyclo[4.2.1.1^2,5]deca-3,7-diene-9,10-dione core. These interesting products are very likely the result of an isoindenone dimerization which was mechanistically studied with the support of DFT calculations. Under the strongly acidic reaction conditions, a stepwise reaction is likely leading to a protonated isoindenone as reactive intermediate. It may first form a van der Waals complex with a neutral isoindenone before the two regio- and diastereoselective ring forming steps occur. Interestingly, two neutral or two protonated isoindenones are also predicted to dimerize giving the observed pentacyclic product.||||||.

Full text of DOI:10.1002/ejoc.202000116

A Journal of
Accepted Article
Title: Alkoxyallene-Based LANCA Three-Component Synthesis of 1,2-
Diketones, Quinoxalines and Unique Isoindenone Dimers and a
Computational Study of the Isoindenone Dimerization
Authors: Roopender Kumar, Mrinal K. Bera, Reinhold Zimmer, Dieter
Lentz, Hans-Ulrich Reissig, and Ernst-Ulrich Würthwein
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000116
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000116
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10.1002/ejoc.202000116
European Journal of Organic Chemistry
FULL PAPER
Alkoxyallene-Based LANCA Three-Component Synthesis of 1,2-
Diketones, Quinoxalines and Unique Isoindenone Dimers and a
Computational Study of the Isoindenone Dimerization
Roopender Kumar,[a][b] Mrinal K. Bera,[a][c] Reinhold Zimmer,[a] Dieter Lentz,[a] Hans-Ulrich Reissig,*[a]
Ernst-Ulrich Würthwein*[d]
Dedicated to Professor Hiriyakkanavar Ila on the occasion of her 75th birthday
Abstract: A series of β-alkoxy-β-ketoenamides was prepared by the
well established LANCA three-component reaction of lithiated 1-(2-
trimethylsilylethoxy)-substituted allenes, nitriles and α,β-unsaturated
carboxylic acids. The α-tert-butyl-substituted compounds were
smoothly converted into the expected 1,2-diketones by treatment with
trifluoroacetic acid. A subsequent condensation of the 1,2-diketones
with o-phenylenediamine provided the desired highly substituted
quinoxalines in good overall yield. Surprisingly, the α-phenyl-
substituted β-alkoxy-β-ketoenamides investigated afford not only the
expected 1,2-diketones, but also pentacyclic compounds with an anti-
tricyclo[4.2.1.12,5]deca-3,7-diene-9,10-dione core. These interesting
products are very likely the result of an isoindenone dimerization
which was mechanistically studied with the support of DFT
calculations. Under the strongly acidic reaction conditions, a stepwise
reaction is likely leading to a protonated isoindenone as reactive
intermediate. It may first form a van der Waals complex with a neutral
isoindenone before the two regio- and diastereoselective ring forming
steps occur. Interestingly, two neutral or two protonated isoindenones
are also predicted to dimerize giving the observed pentacyclic product.
(N) and carboxylic acids (CA) and provided access to a broad
range of β-alkoxy-β-ketoenamides KE (Scheme 1). These
intermediates with a unique assembly of functional groups were
employed to prepare comprehensive libraries of highly substituted
pyridine,[4] pyrimidine[5] and oxazole derivatives.[6]
Scheme 1. The LANCA three-component synthesis of β-alkoxy-β-ketoenamides
KE starting from lithiated alkoxyallenes (LA), nitriles (N) and carboxylic acids
(CA).
During our studies on the reactivity of different types of β-alkoxy-
β-ketoenamides KE we found that β-(2-trimethylsilylethoxy)-β-
ketoenamides 1 generally undergo a smooth acid-promoted
conversion into the 5-acetyl-substituted oxazole derivatives 2
(Scheme 2). The mechanisms of the formation of β-alkoxy-β-
ketoenamides KE and their transformation into oxazoles 2 have
been discussed in detail in these earlier reports.[1, 6] As side-
product or even as major component, simple hydrolysis of the 2-
trimethylsilylethyl enol ether moiety of 1 furnished 1,2-diketones
3. This side-reaction is generally favored when bulky substituents
R1 such as tert-butyl or 1-adamantyl were introduced via the nitrile
component into 1.[6] In the current study, we investigate the
influence of α,β-unsaturated carboxylic acids which should
incorporate an alkenyl side-chain R2 into oxazoles 2 and/or 1,2-
diketones 3. 1,2-Diketones are versatile starting materials for a
variety of transformations, in particular as precursors for several
classes of heterocycles.[7]
Introduction
In earlier reports we described the discovery[1] and synthetic
exploration of
a novel three-component reaction (LANCA
reaction)[2] that employed lithiated alkoxyallenes (LA),[3] nitriles
[a]
Dr. R. Kumar, Dr. M. K. Bera, Dr. R. Zimmer, Prof. Dr. D. Lentz,
Prof. Dr. H.-U. Reissig
Institut für Chemie und Biochemie
Freie Universität Berlin
Takustrasse 3, 14195 Berlin, Germany
E-mail: hreissig@chemie.fu-berlin.de
Homepage: http://www.bcp.fu-berlin.de/en/chemie/chemie/for-
schung/OrgChem/reissig/index.html
[b]
[c]
Present address: Department of Chemistry, University of
Cambridge, Lensfield Road, CB2 1EW Cambridge, UK
Present address: Department of Chemistry, Indian Institute of
Engineering Science and Technology, Shibpur, PO-Botanic Garden,
Howrah-711 103 (WB), India
[d]
Prof. Dr. E.-U. Würthwein
Organisch-Chemisches Institut and Center for Multiscale Theory
and Computation (CMTC)
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster, Germany
E-mail: wurthwe@uni-muenster.de
Supporting information for this article is given via a link at the end of
the document.
1
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Scheme 4. Trifluoroacetic acid-induced conversion of α-tert-butyl-substituted β-
alkoxy-β-ketoenamides 1e-1i into 1,2-diketones 3e-3i.
Scheme 2. Conversion of β-(2-trimethylsilylethoxy)-β-ketoenamides 1 into
oxazoles 2 and/or 1,2-diketones 3.[6]
With the two phenyl-substituted β-alkoxy-β-ketoenamides 1j and
1k, the expected 1,2-diketones 3j and 3k were obtained in
approximately 30% yield, whereas for the N-acetyl derivative 1l
only trace amounts of the corresponding1,2-diketone 3l were
detected in the crude product mixture (Scheme 5). Instead,
oxazole 2l was isolated in 15% yield. No oxazole derivatives were
observed in the reactions of 1j and 1k, as opposed to the smooth
conversion of β-alkoxy-β-ketoenamides with R1 = R2 = Ph or with
R1 = Ph, R2 = C≡CH, where the corresponding 2,4-diphenyl-
substituted or 2-ethynyl-4-phenyl-substituted oxazole derivatives
were isolated in good yield.[6]
Results and Discussion
It has been demonstrated earlier that α,β-unsaturated carboxylic
acids, including the sensitive acrylic acid, are well tolerated in the
LANCA
three-component
reaction
employing
simple
alkoxyallenes. The resulting products were smoothly transformed
into pyridine and pyrimidine derivatives that now bear the
corresponding alkenyl substituent introduced with the carboxylic
acid.[8] When 1-(2-trimethylsilylethoxy)-substituted allene 4 was
treated with n-butyllithium and subsequently with nitriles and α,β-
unsaturated carboxylic acids, we obtained the expected β-alkoxy-
β-ketoenamides 1e-1k in moderate yields, possibly diminished by
formation of side-products possibly in this step (Scheme 3). No
attempts to optimize the process have been undertaken. For
comparison, we also prepared N-acetyl substituted compound 1l
lacking the unsaturated side chain.
Scheme 5. Trifluoroacetic acid-induced conversion of α-phenyl-substituted β-
alkoxy-β-ketoenamides 1j–1l into 1,2-diketones 3j and 3k or oxazole 2l as well
as “dimeric” compounds 5j–5l.
Scheme 3. The LANCA three-component synthesis of β-(2-trimethylsilylethoxy)-
β-ketoenamides 1e-1l.
Surprisingly, in the three experiments a second major product was
isolated in 12-30% yield. By spectroscopy, the structure of 5j, 5k,
and 5l could not be determined unambiguously, although mass
spectrometry indicated a “dimeric compound”, formally arising
from two molecules of 3j–3l and elimination of two molecules of
water. An unequivocal structural elucidation was possible by an
X-ray analysis of compound 5j (Figure 1), showing that a
compound with a C2-symmetric anti-tricyclo[4.2.1.12,5]deca-3,7-
diene-9,10-dione core was formed.[9] Due to the high similarity of
the NMR data of 5j with those of 5k and 5l we can assume that
the latter show the same connectivity of atoms. In the solid state,
compound 5j shows two different hydrogen bridges, one of N1-H
with the carbonyl group of opposite amide side chain, and the
second one of N2-H to the C5 carbonyl group.
Next we examined the acid-promoted reactions of the newly
prepared β-alkoxy-β-ketoenamides 1e-1l. By treatment with
trifluoroacetic acid at 80 °C the five tert-butyl-substituted
compounds 1e-1i gave the expected 1,2-diketones 3e-3i in good
yields (Scheme 4). The bulky substituent R1 apparently
suppresses cyclization to the corresponding oxazole derivatives
2, although we cannot rigorously exclude formation of small
amounts of these compounds. During oxazole formation the
amide carbonyl group functions as the electrophilic unit;
apparently, the conjugation with the double bonds reduces the
electrophilicity of the amide group. We therefore tried to enhance
the reactivity by using o-nitrocinnamic acid as precursor. However,
after treatment of β-alkoxy-β-ketoenamide 1h with trifluoroacetic
acid only the 1,2-diketone 3h was isolated in moderate yield.
2
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10.1002/ejoc.202000116
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indicating that its formation does not involve the 1,2-diketone as
intermediate. A speculative but plausible mechanistic scenario is
depicted in Scheme 6. The deprotection of β-alkoxy-β-
ketoenamides 1 with acid (under desilylation and ethylene
deliberation) first provides the corresponding E-Enol
intermediates that can undergo a rapid (acid-catalyzed) E/Z
isomerization delivering Z-Enols in equilibrium. Only enols with
Z-configuration are able to undergo cyclizations involving the
proximate amide carbonyl group to give oxazole derivatives 2.[6]
For intermediates with bulky groups R1 the E/Z-equilibrium is
shifted to the E-Enols, possibly because of steric repulsion
between R1 and the acetyl group. Therefore, these compounds
provide mainly the 1,2-diketones 3 after a proton shift. For
compounds with R1 = phenyl, the Z-Enols can be protonated to
intermediate A that undergoes an intramolecular electrophilic
substitution at the aromatic ring to afford stabilized σ-complex B.
Water elimination and deprotonation generates the 1-amido-
substituted isoindenone (2-indenone) C as next species.
It is well known that isoindenones are highly reactive
and undergo (reversible) dimerization reactions to form
compounds with a central anti-tricyclo[4.2.1.12,5]deca-3,7-diene-
9,10-dione core.[11-13] This dimerization process can be regarded
as [8π + 8π] or as [4π + 4π] cycloaddition that are formally
forbidden by the Woodward-Hoffmann rules. Alternatively, it can
be described as formally allowed [8π + 2π] cycloaddition if the
oxyallyl cation moiety of the zwitterionic formula of C is considered.
In our cases, the dimerizations leading to compounds 5 may also
proceed under the influence of the strong acid trifluoroacetic acid.
Fig. 1. Solid state structure of 5j (ORTEP plot 50% probability level)[10]
.
The formation of compounds 5j–5l is apparently due to the
presence of the phenyl group of 1j–1l that underwent a cyclization
reaction with the methyl-substituted carbonyl group followed by
further steps. Interestingly, treatment of 1,2-diketone 3k with
trifluoroacetic acid did not lead to the “dimer” 5k, an observation
A
detailed discussion of this process will follow under
consideration of the DFT calculations (see below).
Scheme 6. Scenario for the formation of 1,2-diketones 3, oxazoles 2, isoindenones C and their dimers 5.
We have already demonstrated that 1,2-diketones with general
structure 3 and o-phenylenediamine smoothly form quinoxalines
6.[6b] We employed cerium(IV) ammonium nitrate in water as
promoter of this reaction[14] which also provided the five new
3
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10.1002/ejoc.202000116
European Journal of Organic Chemistry
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quinoxalines 6e–6g, 6i, and 6k in 42-58% yield (Scheme 7).
Alternative methods possibly delivering higher yields were not
examined. These typical examples prove that α,β-unsaturated
substituents R2 are compatible with the mild reaction conditions.
The double bonds of the new quinoxaline derivatives 6 should
allow further diversification of these heterocycles.[15]
Scheme 8. Relative energies of phenyl-substituted enols, 1,2-diketone 3,
oxazole 2 and isoindenone C (relative Gibbs free enthalpies ΔG298 are given in
kcal/mol; values in blue refer to PCM-water calculations).
Scheme 7. Syntheses of quinoxalines 6 by condensation of 1,2-diketones 3 with
o-phenylenediamine.
In Scheme 9 the energetics of the formation of isoindenone C
from Z-Enol are summarized. The protonated species A provides
via transition state TS A-B the σ-complex B, showing that this
electrophilic substitution is slightly endergonic passing a relatively
low energy barrier of 17.4 kcal/mol. The final water elimination to
C+H+ is almost energetically neutral, probably as result of
compensation of the antiaromatic character of C+H+ and the
stability of the formed water molecule. Aggregation of water
molecules (not considered here) certainly will make this step
energetically even more favorable. For the last step (removal of
the hydroxonium ion) the calculated data indicate the enormous
basicity of compound C and also the solvent influence on this
acid-base equilibrium.
Mechanistic Investigation by DFT Calculations
In order to investigate how realistic the reaction mechanisms
shown in Scheme 6 are, quantum chemical DFT model
calculations for compounds 2 and 3 with R1 = Ph and R2 = H (see
Scheme 2) and for 5 with R3 = NHCHO (see Scheme 5) were
performed.[16] On the basis of B3LYP/6-31G(d)[17] + GD3BJ[18]
geometry optimizations TPSSTPSS/def2tzvp[19]
+
GD3BJ
optimizations for the gas phase were performed. In accord with
the reaction conditions (thermal reactions) only closed shell
calculations were performed, although diradical intermediates
cannot be excluded. The modeling of the highly acidic
trifluoroacetic acid as reaction solvent and medium is not trivial
using the PCM procedure.[20] Therefore, PCM calculations
(including geometry optimizations) using a solvent sphere of
water as highly polar solvent were done in order to estimate the
influence of
a highly polar environment on the reaction
mechanism and also on the intermediates and products after
aqueous workup. In the following, we discuss Gibbs free energies
[kcal/mol], for the PCM-water model the data are given in italics
[kcal/mol](see also Supporting Information for details).
In Scheme 8 the thermodynamic properties of the neutral
phenyl-substituted E-Enol, Z-Enol, 1,2-diketone 3, oxazole 2 and
isoindenone C are compared. Whereas the enols and the diketo
form 3 as well as the oxazole derivative 2 are close in energy,
interestingly the isoindenone C is much less stable, reflecting the
ortho-chinodimethane substructure of this highly reactive
intermediate (see below). The endothermicity of the later
conversion indicates the necessity of proton catalysis for the next
steps.
Scheme 9. Formation of C-H+ starting from protonated species A via σ-complex
B (relative Gibbs free enthalpies ΔG298 are given in kcal/mol); values in blue
refer to PCM-water calculations).
4
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10.1002/ejoc.202000116
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FULL PAPER
To estimate the thermodynamics of the regio- and
diastereoselective isoindenone dimerization with respect to the
stability of the four possible isoindenone dimers 5–5´´´ Scheme
10 shows the calculated Gibbs free reaction enthalpies. All dimers
5–5´´´ incorporate two pairs of neighbored quaternary carbons.
dimer 5´ and the two syn-dimers 5´´ and 5´´´. Besides the syn-
anti arrangement the dimers display different possibilities for
hydrogen bonding, thus influencing the energetics of the isomers.
Various possibilities were tested starting with the experimentally
found structure of 5j (X-ray), which came out to be best in energy.
In accordance with the reaction conditions (trifluoroacetic
acid as reaction medium), three different scenarios were
considered: dimerization of two neutral molecules C, reaction of
C with C+H+, and finally dimerization of two protonated forms
C+H+. A mechanistic picture of the stepwise dimerization of
neutral C is shown in Scheme 11. At first, the exothermic
formation of van der Waals complexes of two isoindenones is
assumed, offering various possibilities for bond formation at the
different α-carbon atoms to the isoindenone carbonyl functions.
Quantum chemical pathway calculations indicate a stepwise
mechanism (due to the asymmetric substitution pattern of the
isoindenones employed). For the experimentally observed
structure 5 a C-C bond formation between the two methyl-
substituted α-carbon atoms turned out to be preferred. This
reflects the higher reactivity of the methyl-substituted carbon
atoms. The alternative approach of bond formation between the
two formamide-substituted C-atoms is less favorable, most likely
due to lower stabilization in the resulting intermediate. The
reaction barrier TS1 C-D is calculated to be surprisingly low,
indicating the high reactivity of the isoindenone, leading to a quite
stable intermediate D. The next step, forming of the second C-C-
bond also requires only a small barrier (TS2 D-5) leading to the
observed product 5 with anti positioned carbonyl moieties as the
thermodynamically most stable species within this reaction
sequence. Overall, there is only a small influence of the solvent
polarity on the free enthalpies.
Scheme 10. Energies of dimers 5–5´´´ of isoindenone C (relative Gibbs free
enthalpies ΔG298 are given in kcal/mol; values in blue refer to PCM-water
calculations).
The values clearly reveal the high exothermicity of the
dimerization reaction with the isolated head-to-head anti-dimer 5
being the most stable isomer, followed by the head-to-tail anti-
Scheme 11. Stepwise dimerization of neutral C via van der Waals complex (C + C) and transition state TS1 C-D to intermediate D followed by transition state TS2
D-5 to isoindenone dimer 5 (relative Gibbs free enthalpies ΔG298 are given in kcal/mol); values in blue refer to PCM-water calculations).
5
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10.1002/ejoc.202000116
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FULL PAPER
In a similar way the reaction of one neutral molecule C with its
protonated form C+H+ and the dimerization of two C+H+
molecules were investigated (Table 1, columns 3 and 4), following
the same reaction sequence as studied for the dimerization of C.
The formation of the van der Waals complex from C and C+H+ is
much more exothermic, thus reflecting the favorable neutral-
cation interaction. Again, over a very small barrier TS1 a quite
stable intermediate D+H+ was localized, which led to the product
5+H+ over
a second relatively low transition state TS2.
Surprisingly, product 5+H+ is higher in energy compared to D+H+,
possibly due to the less pronounced conjugation in the product.
Of course, deprotonation during the experimental procedure
(aqueous workup) may form 5 by shifting the equilibrium towards
this product.
Scheme 12. Stepwise reaction of C and C+H+ via van der Waals complex (C + C-H+) and transition state TS1 to intermediate D+H+ followed by transition state TS2
to protonated dimer 5+H+ (relative Gibbs free enthalpies ΔG298 are given in kcal/mol; values in blue refer to PCM-water calculations).
Table 1. Summary of the reactions of two neutral molecules C, of a neutral molecule C with a protonated molecule C+H+ and of two protonated molecules C+H+ to
give the respective compounds 5, 5+H+ and 5+2H+ (relative Gibbs free enthalpies ΔG298 in kcal/mol), Column 2,4 and 6: gas phase calculations, columns 3, 5 and
7: PCM-model for water as solvent, values in blue).
Neutral species
2*C
Monocations
C + C+H+
Dications
2* C+H+
Erel [kcal/mol] Erel [kcal/mol] Erel [kcal/mol] Erel [kcal/mol] Erel [kcal/mol] Erel [kcal/mol]
gas phase
PCM-H2O
gas phase
PCM-H2O
gas phase
PCM-H2O
Starting
material
5.7
7.2
36.3
26.8
-21.6
24.3
van der
Waals
Complex
0.0
2.9
0.0
1.6
0.0
1.5
0.0
1.2
0.0
0.0
7.4
-9.9
6.8
3.7
TS1
11.4
-5.5
18.1
15.4
Intermediate
TS2
-28.4
-24.1
-31.0
-25.0
-19.4
-28.5
-13.3
0.9
-14.6
-0.4
-4.0
Product
-5.5
6
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10.1002/ejoc.202000116
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For completeness, the reaction of two molecules of C+H+ was
also studied, modeling the dimerization of two protonated
isoindenones in the reaction medium trifluoroacetic acid (Table 1,
columns 5 and 6, for a Scheme, see Supporting information).
Interestingly, in spite of the two positive charges, a van der Waals
complex could be localized, leading via a relatively low TS to a
stable intermediate D+2H+. The later may be transformed via a
reasonable TS into the doubly protonated product 5+2H+, which
is in the gas phase quite high in energy. Not surprisingly, the
PCM-water model influences the energetics of the reaction of
these two charged species tremendously. Thus, the formation of
the van der Waals complex is highly endothermic in the gas phase
(repulsion of the two charges), but exothermic according to the
PCM water model. The transition state TS1 corresponds to a
medium barrier and leads exothermically to the intermediate. The
second barrier TS2 is calculated to be higher compared to the first
one (TS1), but still in accord with the reaction conditions applied
(80 °C). The doubly protonated product is high in energy,
indicating that only small amounts of it may be present in the
equilibrium. Again, deprotonation of 5+2H+ may remove the
neutral product 5 from the reaction mixture.
Interestingly, in all three cases stepwise reactions with
relatively stable intermediates and two well defined transition
states were found. Thermodynamically the formation of the first
C-C bond between the methyl-substituted isoindenone carbon
atoms is favored over the bonding of the NHCHO-substituted
isoindenone carbon atoms. A synchronous (concerted) 4+4
pericyclic reaction pathway of the asymmetric C could not be
detected, in accordance with the Woodward-Hoffmann-rules.
From the thermodynamic and kinetic point of view, all three
reaction pathways for the dimerization are calculated to be
compatible with the reaction conditions. Thus, strong acid seems
not to be a precondition for the success of the dimerization. In
contrast, a basic component (e.g. C) or byproduct or aqueous
workup seem to be necessary to transfer protonated
intermediates 5+H+ or 5+2H+ in the final neutral products 5.
However, it should be noted that the formation of isoindenone C
necessarily requires acidic conditions (Scheme 9).
As alternative to the isoindenone-dimerization other
mechanisms may also take place, e. g. an isoindenone unit may
react with an open-chain intermediate (Scheme 13). Thus, the
thermodynamics of various other reaction pathways of positively
charged species were studied computationally. The reaction of C
with protonated 1,2-diketone 3+H+ affords a positively charged
intermediate E which is formally a water addition product of D+H+
[-39.5 kcal/mol (gas phase), -24.1 kcal/mol (PCM-H2O); for details
and a Scheme see Supporting information]. As second possibility
to give intermediate E, the reaction of C+H+ with the Z-enol was
calculated to be less exothermic [-20.0 kcal/mol (gas phase), -7.6
kcal/mol (PCM-H2O)]. Finally, the combination of C+H+ with 1,2-
diketone 3 also may give E [-18.8 kcal/mol (gas phase), -7.0
kcal/mol (PCM-H2O)]. Subsequent conversions of E to give D+H+
and H2O are exothermic (-18.6 kcal/mol / -25.7 kcal/mol (PCM-
H2O) allowing access to the product 5+H+ (see above, Scheme
11). In summary, all three alternative mechanisms are exothermic
with respect to the starting materials. Unfortunately, all attempts
the calculate the kinetics for the formation of E and D+H+ were
unsuccessful.
Scheme 13. Alternative pathways to give intermediate E and the subsequent
products D+H+ and 5+H+.
Conclusions
Expecting standard results for the acid-promoted hydrolysis of β-
alkoxy-β-ketoenamides 1 we serendipitously discovered a new
route to isoindenones. Whereas α-tert-butyl-substituted
compounds 1 and trifluoroacetic acid provided the desired 1,2-
diketones 3 in good yields, the α-phenyl-substituted β-alkoxy-β-
ketoenamides afforded not only the 1,2-diketones, but also
pentacyclic compounds with an anti-tricyclo[4.2.1.12,5]deca-3,7-
diene-9,10-dione core. This was unequivocally proven by an X-
ray analysis of compound 5j. By condensation with o-
phenylenediamine, the 1,2-diketones 3 could be converted under
mild conditions into a series of highly substituted quinoxalines 6.
The unexpectedly isolated compounds 5 were very likely the
result of
a regio- and diastereoselective dimerization of
intermediate isoindenones that are formed by an intramolecular
electrophilic substitution process at the phenyl substituent.
Comprehensive DFT calculations indicate that a stepwise
dimerization process of the neutral isoindenone C via a van der
Waals complex and a zwitterionic intermediate is energetically
feasible. As alternatives, monocationic or even dicationic species
were also considered. Furthermore, a synchronous 4π + 4π
cycloaddition – forbidden by the Woodward Hoffmann rules –
could not be identified as possible pathway. Compounds with the
rigid and functionalized pentacyclic core such as 5 could be
interesting precursors for further synthetic adventures. Their
simple formation from β-alkoxy-β-ketoenamides 1 (or equivalent
precursors) should initiate further studies.
Experimental Section
If not stated otherwise, all reactions were carried out under argon. The
solvents used were purified by distillation using common drying agents and
procedures and were transferred under argon. Flash chromatography:
Merck silica gel 60 (230-400 mesh). NMR: Spectra were recorded with AC
500 (Bruker), ECP 500 and ECX 400 (Jeol) spectrometers in the solvents
indicated; chemical shifts (δ) are given in ppm relative to residual solvent
peaks, coupling constants (J) are given in Hz. IR spectra were recorded
with a Nicolet-FT-IR spectrometer or 5 SXC spectrometer, wavenumbers
are given in cm-1. Mass spectra were recorded with MAT 711 (EI, 80 eV, 8
kV), MAT CH7A (EI, 80 eV, 3 kV), CH5DF (FAB, 3 kV) (all Finnigan),
Ionspec QFT-7 (ESI-FT ICRMS) (Varian) and Agilent 6210 (ESI-TOF, 4
μL/min, 1.0 bar, 4 kV). Melting points: Thermovar (Reichert) melting point
apparatus (not corrected). Elemental analyses: Elemental Analyzer
(Perkin-Elmer), Vario EL elemental analysis system. All commercially
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000116
European Journal of Organic Chemistry
FULL PAPER
available compounds (Acros, Lancaster, Fluka, Aldrich, TCI Europe) were
used as received unless stated otherwise.
tBu), 2.31 (s, 3 H, Me), 3.51–3.55 (m, 2 H, OCH2), 6.48 (d, J = 15.5 Hz, 1
H, =CH), 7.38–7.54, 7.84–7.92 (2 m, 2 H, 3 H, Ar, =CH) ppm; IR (neat): 
= 3285 (NH), 2960-2875 (=C-H, C-H), 1685–1630 (C=O, C=C) cm-1;
HRMS: m/z [M + H]+ calcd. for C22H33N2O5Si: 433.2159; found: 433.2153.
(E)-N-{2,2-Dimethyl-5-oxo-4-[2-(trimethylsilyl)ethoxy]hex-3-en-3-
yl}acrylamide (1e), Typical Procedure 1: To a solution of TMSE-allene
4 (2.63 mL, 18.0 mmol) in dry diethyl ether (25 mL) was added n-
butyllithium (7.18 mL, 18.0 mmol, 2.5 M in hexanes) at –50 °C. After 30
min stirring at this temperature, the mixture was cooled to –78 °C and
pivalonitrile (0.50 g, 6.02 mmol) in dry diethyl ether (6 mL) was added.
After stirring for 4 h at the same temperature, a solution of acrylic acid
(2.16 g, 36.0 mmol) in dry diethyl ether (10 mL) was added to the reaction
mixture. The temperature was allowed to rise to room temperature and the
mixture was stirred overnight. The reaction was quenched with sat. aq.
NaHCO3 solution (30 mL) and the product was extracted with diethyl ether
(3×80 mL). The combined organic layers were washed with brine (35 mL)
and finally dried (Na2SO4). The solvent was removed in vacuo and the
crude product was purified by column chromatography (silica gel,
hexanes/ethyl acetate = 2:1) to obtain β-ketoenamide 1e as pale yellow
solid (0.75 g, 40%). M. p. 93–96 °C; 1H NMR (500 MHz, CDCl3): δ = 0.00
(s, 9 H, SiMe3), 1.05–1.08 (m, 2 H, SiCH2), 1.22 (s, 9 H, tBu), 2.23 (s, 3 H,
Me), 3.57–3.60 (m, 2 H, OCH2), 5.59 (dd, J = 10.5, 1.7 Hz, 1 H, =CHCO),
6.11–6.22 (m, 2 H, =CH2), 7.40 (s, 1 H, NH) ppm; 13C NMR (125 MHz,
CDCl3): δ = –1.4 (q, SiMe3), 18.7 (t, CH2Si), 22.1 (q, Me), 28.5, 36.4 (q, s,
tBu), 69.4 (t, CH2O), 127.5, 130.5, 131.7, 150.3 (t, d, 2 s, C-2´, C-3´, C-1,
C-2), 165.3 (s, C-1´), 201.5 (s, C-3) ppm; IR (KBr):  = 3300 (NH), 2950–
2855 (=C-H, C-H), 1685–1625 (C=O, C=C) cm-1; HRMS: m/z [M + Na]+
calcd. for C16H29NO3NaSi: 334.1809; found: 334.1826; C16H29NO3Si
(311.1): calcd. C, 61.69, H, 9.38, N, 4.50; found C, 61.67; H, 9.20; N, 4.20.
(E)-N-{(E)-2,2-Dimethyl-5-oxo-4-[2-(trimethylsilyl)ethoxy]hex-3-en-3-
yl)-3-(furan-2-yl)acrylamide (1i): According to typical procedure 1, a
mixture of TMSE-allene 4 (2.63 mL, 18.0 mmol), n-butyllithium (7.18 mL,
18.0 mmol, 2.5 M in hexanes), pivalonitrile (0.66 mL, 6.0 mmol) and 3-(2-
furyl)acrylic acid (4.98 g, 36.0 mmol) in dry diethyl ether (40 mL) gave
0.680 g (30%) of β-ketoenamide 1i as a pale yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 0.00 (s, 9 H, SiMe3), 1.06–1.10 (m, 2 H, SiCH2), 1.20 (s, 9 H,
tBu), 2.27 (s, 3 H, Me), 3.59–3.64 (m, 2 H, OCH2), 6.32–6.35 (m, 2 H, =CH,
Furyl), 6.43 (d, J = 3.3 Hz, 1 H, Furyl), 7.30 (d, J = 15.3 Hz, 1 H, =CH),
7.35 (m, 2 H, NH, Furyl); 13C NMR (100 MHz, CDCl3): δ = –1.4 (q, SiMe3),
18.8 (t, CH2Si), 27.9, 28.6, 36.4 (2 q, s, Me, tBu), 69.5 (t, CH2O), 112.1,
114.0 (2 d, C-3Furyl, C-4Furyl), 118.0, 128.9, 131.9, 144.1, 150.0, 151.3 (3 d,
3 s, C-2´, C-3´, C-2, C-3, C-2Furyl, C-5Furyl), 168.2 (s, C-1´), 201.2 (s, C-3)
ppm; IR (neat):  = 3220 (NH), 2955–2870 (=CH, C-H), 1702–1620 (C=O,
C=C) cm-1; HRMS: m/z [M + Na]+ calcd. for C20H31NO4NaSi: 400.1920;
found: 400.1927.
(E)-N-{(E)-3-Oxo-1-phenyl-2-[2-(trimethylsilyl)ethoxy]but-1-enyl}but-
2-enamide (1j): According to typical procedure 1, a mixture of TMSE-
allene 4 (2.12 mL, 14.5 mmol), n-butyllithium (5.81 mL, 14.5 mmol, 2.5 M
in hexanes), benzonitrile (0.50 g, 4.85 mmol) and crotonic acid (1.99 mL,
23.1 mmol) in dry diethyl ether (40 mL) gave 0.845 g (46%) of β-
ketoenamide 1j as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ = –0.17
(s, 9 H, SiMe3), 0.62–0.66 (m, 2 H, SiCH2), 1.85 (dd, J = 6.8, 1.7 Hz, 3 H,
Me), 2.34 (s, 3 H, Me), 3.26–3.31 (m, 2 H, OCH2), 5.92 (dd, J = 15.2, 1.4
Hz, 1 H, =CH), 6.79–6.88 (m, 1 H, =CH), 7.25–7.42 (m, 5 H, Ph), 11.45 (s,
1 H, NH) ppm; 13C NMR (100 MHz, CDCl3): δ = –1.6 (q, SiMe3), 18.0 (q,
C-4´), 18.7 (t, CH2Si), 27.5 (q, Me), 71.4 (t, CH2O), 125.9, 127.7, 128.4,
128,7, 132.7, 137.3, 142.7, 143.1 (5 d, 3 s, C-2´, C-3´, C-1, C-2, Ph), 164.2
(s, C-1´), 202.5 (s, C-3) ppm; IR (neat):  = 3305 (NH), 3015–2955 (=C-H,
C-H), 1700–1565 (C=O, C=C) cm-1; HRMS: m/z [M + Na]+ calcd. for
C19H27NO3NaSi: 368.1658; found: 368.1650.
(E)-N-{(E)-2,2-Dimethyl-5-oxo-4-[2-(trimethylsilyl)ethoxy]hex-3-en-3-
yl}but-2-enamide (1f): According to typical procedure 1, a mixture of
TMSE-allene 4 (2.63 mL, 18.0 mmol), n-butyllithium (7.18 mL, 18.0 mmol,
2.5 M in hexanes), pivalonitrile (0.66 mL, 6.0 mmol) and crotonic acid (2.58
g, 30.0 mmol) in dry Et2O (35 mL) gave 0.823 g (42%) of β-ketoenamide
1f as a pale yellow oil. 1H NMR (500 MHz, CDCl3): δ = 0.01 (s, 9 H, SiMe3),
1.06–1.10 (m, 2 H, SiCH2), 1.20 (s, 9 H, tBu), 1.82 (dd, J = 6.8, 1.7 Hz, 3
H, Me), 2.24 (s, 3 H, Me), 3.60–3.63 (m, 2 H, OCH2), 5.83 (dq, J = 15.1,
1.7 Hz, 1 H, =CH), 6.78–6.85 (m, 1 H, =CH), 6.92 (sbr, 1 H, NH); 13C NMR
(125 MHz, CDCl3): δ = –1.4 (q, SiMe3), 17.8 (q, C-4´), 18.8 (t, CH2Si), 22.2
(q, Me), 28.5, 36.4 (q, s, tBu), 69.4 (t, CH2O), 124.7, 132.4, 141.5, 150.0
(2 d, 2 s, C-2´, C-3´, C-1, C-2), 165.7 (s, C-1´), 201.2 (s, C-3) ppm; IR
(neat):  = 3265 (NH), 2955–2850 (=CH, C-H), 1670–1630 (C=O, C=C)
cm-1; HRMS: m/z [M + Na]+ calcd. for C17H31NO3NaSi: 348.1971; found:
348.1979.
N-{(E)-3-Oxo-1-phenyl-2-[2-(trimethylsilyl)ethoxy]but-1-enyl}-
cinnamamide (1k): According to typical procedure 1, a mixture of TMSE-
allene 4 (2.12 mL, 14.5 mol), n-butyllithium (5.81 mL, 14.5 mmol, 2.5 M in
hexanes), benzonitrile (0.50 g, 4.85 mmol) and cinnamic acid (4.31 g, 29.1
mmol) in dry diethyl ether (40 mL) gave 1.00 g (50%) of β-ketoenamide 1k
as a pale yellow solid. M. p. 68–72 °C; 1H NMR (400 MHz, CDCl3): δ =
–0.14 (s, 9 H, SiMe3), 0.66–0.70 (m, 2 H, SiCH2), 2.38 (s, 3 H, Me), 3.32–
3.36 (m, 2 H, OCH2), 5.54 (d, J = 15.6 Hz, 1 H, =CH), 7.34–7.42, 7.46–
7.51 (2 m, 6 H, 4 H, Ph), 7.71 (d, J = 15.6 Hz, 1 H, =CH), 11.72 (s, 1 H,
NH) ppm; 13C NMR (100 MHz, CDCl3): δ = –1.5 (q, SiMe3), 18.7 (t, CH2Si),
27.6 (q, Me), 71.5 (t, CH2O), 121.0, 127.8, 128.2, 128.5, 128.7, 128.9,
130.2, 132.7, 134.5, 137.4, 143.1, 143.4 (6 d, 4 s, 2 d, C-2´, C-3´, C-1,
C-2, Ph), 164.3 (s, C-1´), 202.6 (s, C-3) ppm; IR (KBr):  = 3275 (NH),
3065–2895 (=C-H, C-H), 1695–1630 (C=O, C=C) cm-1; HRMS: m/z [M +
Na]+ calcd. for C24H29NO3NaSi: 430.1809; found: 430.1825; C24H29NO3Si
(407.6): calcd. C, 70.72, H, 7.17, N, 3.44; found: C, 70.07, H, 6.10, N, 3.20.
N-{(E)-2,2-Dimethyl-5-oxo-4-[2-(trimethylsilyl)ethoxy]hex-3-en-3-
yl}cinnamamide (1g): According to typical procedure 1, a mixture of
TMSE-allene 4 (2.63 mL, 18.0 mmol), n-butyllithium (7.18 mL, 18.0 mmol,
2.5 M in hexanes), pivalonitrile (0.50 g, 6.02 mmol) and cinnamic acid (4.98
g, 36.0 mmol) in dry diethyl ether (40 mL) gave 0.814 g (35%) of β-
ketoenamide 1g as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ = 0.03
(s, 9 H, SiMe3), 0.96–0.98 (m, 2 H, SiCH2), 1.26 (s, 9 H, tBu), 2.28 (s, 3 H,
Me), 3.63–3.68 (m, 2 H, OCH2), 6.42 (d, J = 15.5 Hz, 1 H, =CH), 6.98( s,
1 H, NH), 7.34, 7.47–7.49 (mc, m, 3 H, 2 H, Ph), 7.60 (d, J = 15.5 Hz, 1 H,
=CH) ppm; 13C NMR (125 MHz, CDCl3): δ = –1.3 (q, SiMe3), 18.9 (t, CH2Si),
25.9 (q, C-4´), 28.7, 36.6 (q, s, tBu), 69.7 (t, CH2O), 128.1, 128.9, 129.1,
129.9, 132.4, 134.8, 142.5, 150.1 (2 s, d, s, 4 d, C-2´, C-3´, C-1, C-2),
166.0 (s, C-1´), 201.4 (s, C-3) ppm; R (neat):  = 3285 (NH), 2955-2865
(=C-H, C-H), 1690–1635 (C=O, C=C) cm-1; HRMS: m/z [M + Na]+ calcd.
for C22H33NO3NaSi: 410.2127; found: 410.2135.
(E)-N-(3-Oxo-1-phenyl-2-(2-(trimethylsilyl)ethoxy)but-1-enyl)acet-
amide (1l): According to typical procedure 1, a mixture of TMSE-allene 4
(0.58 mL, 4.00 mmol), n-butyllithium (1.4 mL, 3.50 mmol, 2.5 M in
hexanes), benzonitrile (0.50 g, 4.85 mmol) and acetic acid (0.75 mL, 9.60
mmol) in dry diethyl ether (20 mL) gave 0.255 g (23%) of β-ketoenamide
1l as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ = –0.17 (s, 9 H, SiMe3),
0.62–0.67 (m, 2 H, SiCH2), 2.07, 2.34 (2 s, 3 H each, Me), 3.25–3.30 (m,
2 H, OCH2), 7.35–7.40 (m, 5 H, Ph), 11.2 (s, 1 H, NH) ppm; 13C NMR (100
MHz, CDCl3): δ = –1.6 (q, SiMe3), 18.7 (t, CH2Si), 25.0, 27.6 (2 q, Me),
71.4 (t, CH2O), 127.8, 128.6, 128.8, 132.7, 137.4, 142.3 (3 d, 3 s, C-2´, C-
3´, Ph), 169.0 (s, C-1´), 202.5 (s, C-3) ppm; IR (neat):  = 3270 (NH), 3060–
2890 (=C-H, C-H), 1685–1630 (C=O, C=C) cm-1; HRMS: m/z [M + Na]+
calcd. for C17H25NO3NaSi: 342.1496; found: 342.1486.
(E)-N-{(E)-2,2-Dimethyl-5-oxo-4-[2-(trimethylsilyl)ethoxy]hex-3-en-3-
yl}-3-(4-nitrophenyl)acrylamide (1h): According to typical procedure 1, a
mixture of TMSE-allene 4 (2.70 mL, 18.6 mmol), n-butyllithium (7.20 mL,
18.0 mmol, 2.5 M in hexanes), pivalonitrile (0.50 g, 6.02 mmol) and 2-
nitrocinnamic acid (6.98 g, 36.0 mmol) in dry diethyl ether (35 mL) gave
1.37 g (52%) of β-ketoenamide 1h as a pale yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 0.00 (s, 9 H, SiMe3), 1.06–1.10 (m, 2 H, SiCH2), 1.21 (s, 9 H,
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000116
European Journal of Organic Chemistry
FULL PAPER
N-(2,2-Dimethyl-4,5-dioxohexan-3-yl)acrylamide
(3e),
Typical
cm-1; HRMS: m/z [M + Na]+ calcd. for C15H19NO4Na: 300.1212; found:
procedure 2: β-Ketoenamide 1e (160 mg, 0.514 mmol) and trifluoroacetic
acid (5 mL) were heated to 80 °C in a sealed tube for 15 min. After cooling
to room temperature, water was slowly added and the resulting mixture
was extracted 2–3 times with dichloromethane. The combined organic
layers were dried with Na2SO4, filtered and concentrated. Purification by
column chromatography (SiO2, hexanes/EtOAc 40%) provided 79 mg
(73%) of 1,2 diketone 3e as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ
= 0.94 (s, 9 H, tBu), 2.32 (s, 3 H, Me), 5.25 (d, J = 7.6 Hz, 1 H, CH), 5.64
300.1233.
(E)-N-(2,3-Dioxo-1-phenylbutyl)but-2-enamide (3j) and compound 5j:
According to typical procedure 2, enamide 1j (430 mg, 1.25 mmol) in
trifluoroacetic acid (5 mL) gave 91 mg (30%) of 1,2-diketone 3j as pale
yellow oil and 84 mg (30%) of compound 5j as pale yellow solid. Data for
3j: 1H NMR (400 MHz, CDCl3): δ = 1.82–1.84 (m, 3 H, =CHMe), 2.28 (s, 3
H, COMe), 5.83–5.87 (m, 1 H, =CHCO), 6.21 (d, J = 5.6 Hz, 1 H, CH), 6.46
(sbr, 1 H, NH), 6.79–6.88 (m, 1 H, =CHMe), 7.29–7.34 (m, 5 H, Ph) ppm;
13C NMR (100 MHz, CDCl3): δ = 17.8 (q, Me), 24.3 (q, 3´-Me), 57.5 (d, C-
1), 123.8, 128.5, 128.9, 129.3, 134.0, 141.7 (5 d, s, C-2´, C-3´, Ph), 165.5
(s, C-1´), 192.8, 196.1 (2 s, C-2, C-3) ppm; IR (neat):  = 3305 (NH), 3020–
2835 (=C-H, C-H), 1700, 1675 (C=O), 1640–1505 (C=C) cm-1; HRMS: m/z
[M + Na]+ calcd. for C14H15NO3Na: 268.0950; found: 268.0986. Data for
dimer 5j: M. p. > 220 °C; 1H NMR ( 400 MHz, CDCl3): δ = 1.41 (s, 6 H, Me),
1.88 (d, J = 6.8 Hz, 6 H, Me), 6.00 (d, J = 15.2 Hz, 2 H, =CH), 6.87–6.96
(m, 2 H, =CH), 7.27–7.37 (m, 6 H, Ar), 7.69 (d, J = 7.2 Hz, 2 H, Ar), 8.19
(sbr, 2 H, NH) ppm; 13C NMR (100 MHz, CDCl3): δ = 9.5 (q, Me), 17.9 (q,
Me), 57.1 (s, C-1), 72.2 (s, C-3), 122.3, 124.4, 124.7, 129.2, 129.6, 137.9,
139.0, 142.1 (6 d, 2 s, C-2´, C-3´, Ar), 167.2 (s, C-1´), 199.2 (s, C-2) ppm;
IR (KBr):  = 3355 (NH), 3020–2875 (=C-H, C-H), 1775, 1680 (C=O),
1640–1505 (C=C) cm-1; HRMS: m/z [M + Na]+ calcd. for C28H27N2O4Na:
477.1868; found: 477.1829.
(dd, J = 9.2, 1.6 Hz, 1 H, =CH2), 6.10–6.27 (m, 3 H, =CH2, NH) ppm; 13
C
NMR (100 MHz, CDCl3): δ = 23. 4 (q, Me), 26.7, 35.0 (q, s, tBu), 58.1 (d,
C-1), 127.6, 129.8 (d, t, C-2´, C-3´), 165.5 (s, C-1´), 196.3, 198.1 (2 s,
C-2, C-3) ppm; IR (neat):  = 3300 (NH), 2960–2855 (=C-H, C-H), 1710–
1660 (C=O), 1620–1530 (C=C) cm-1; HRMS: m/z [M + Na]+ calcd. for
C11H17NO3Na: 234.1101; found: 234.1105.
(E)-N-(2,2-Dimethyl-4,5-dioxohexan-3-yl)but-2-enamide
(3f):
According to typical procedure 2, β-ketoenamide enamide 1f (225 mg,
0.69 mmol), in trifluoroacetic acid (5 mL) gave 124 mg (80%) of 1,2-
diketone 3f as pale yellow solid. M. p. 73–76 °C; 1H NMR (400 MHz,
CDCl3): δ = 0.93 (s, 9 H, tBu), 1.79–1.81 (m, 3 H, Me), 2.31 (s, 3 H, Me),
5.17 (d, J = 7.4 Hz, 1 H, CH), 5.81–5.85 (dd, J = 15.2, 1.1 Hz, 1 H, =CH),
6.11–6.18 (m, 1 H, NH), 6.74–6.83 (m, 1 H, =CH); 13C NMR (100 MHz,
CDCl3): δ = 17.8 (q, C-4), 23.5 (q, Me), 26.7, 34.8 (q, s, tBu), 58.1 (d,
C-1), 124.0, 141.3 (2 d, C-2´, C-3´), 165.9 (s, C-1´), 196.4, 198.1 (2 s,
C-2, C-3) ppm; IR (KBr):  = 3285 (NH), 2960–2865 (=CH, C-H), 1720–
1670 (C=O), 1605–1520 (C=C) cm-1; HRMS: m/z [M + Na]+ calcd. for
C12H19NO3Na: 248.1263; found: 248.1224; C12H19NO5 (225.1): calcd. C,
63.98; H, 6.50; N, 6.22; found: C, 64.48; H, 6.66; N, 5.76.
N-(2,3-Dioxo-1-phenylbutyl)cinnamamide (3k) and Compound 5k:
According to typical procedure 2, enamide 1k (80 mg, 0.196 mmol) in
trifluoroacetic acid (2 mL) gave 19 mg (33%) of 1,2-diketone 3k and 14 mg
(25%) of compound 5k as pale yellow oils. Data for 3k: 1H NMR (400 MHz,
CDCl3): δ = 2.31 (s, 3 H, Me), 6.33 (d, J = 5.8 Hz, 1 H, CH), 6.46 (d, J =
15.6 Hz, 1 H, =CH), 6.63 (sbr, 1 H, NH), 7.25–7.49 (m, 10 H, Ph), 7.62 (d,
J = 15.6 Hz, 1 H, =CH) ppm; 13C NMR (100 MHz, CDCl3): δ = 24.4 (q, Me),
57.7 (d, C-1), 128.0, 128.4, 128.9, 129.0, 129.4, 130.0, 130.7, 133.9, 134.5,
142.5 (8 d, 2 s, C-2´, C-3´, Ph), 165.5 (s, C-1´), 192.8, 196.0 (2 s, C-2,
C-3) ppm; IR (neat):  = 3405 (NH), 3020 (=C-H, C-H), 1705, 1675 (C=O),
1620 (C=C) cm-1; HRMS: m/z [M + Na]+ calcd. for C19H17NO3Na: 330.1106;
found: 330.1156. Data for compound 5k: 1H NMR (400 MHz, CDCl3): δ =
1.46 (s, 6 H, Me), 6.62 (d, J = 15.5 Hz, 2 H, =CH), 7.31–7.37, 7.54–7.56
(2 m, 14 H, 4 H, Ar, Ph), 7.72 (d, J = 15.6 Hz, 2 H, =CH), 8.44 (sbr, 2 H,
NH) ppm; 13C NMR (100 MHz, CDCl3): δ = 9.6 (q, Me), 57.2 (s, C-1), 72.5
(s, C3), 120.1, 122.4, 124.5, 128.2, 128.9, 129.4, 129.7, 130.1, 134.5,
137.9, 139.1, 142.9 (9 d, 3 s, C-2´, C-3´, Ar, Ph), 167.3 (s, C-1´), 199.8 (s,
C-2) ppm; IR (KBr):  = 3340 (NH), 3070–2980 (=C-H, C-H), 1780, 1665
(C=O), 1625-1510 (C=C) cm-1; HRMS: m/z [M + H]+ calcd. for C38H31N2O4:
579.2278; found: 579.2296.
N-(2,2-Dimethyl-4,5-dioxohexan-3-yl)cinnamamide (3g): According to
typical procedure 2, β-ketoenamide 1g (300 mg, 0.775 mmol) in
trifluoroacetic acid (5 mL) gave 133 mg (60%) of 1,2-diketone 3g as pale
yellow solid. M. p. 75–78 °C; 1H NMR (400 MHz, CDCl3): δ = 0.99 (s, 9 H,
tBu), 2.36 (s, 3 H, Me), 5.34 (d, J = 7.4 Hz, 1 H, CH), 6.34 (dbr, J = 4.9 Hz,
1 H, NH), 6.47 (dd, J = 15.6, 1.0 Hz, 1 H, =CH), 7.33–7.35, 7.46–7.49 (2
m, 3 H, 2 H, Ph), 7.60 (d, J = 15.6 Hz, 1 H, =CH) ppm; 13C NMR (100 MHz,
CDCl3): δ = 23.5 (q, Me), 26.8, 35.1 (q, s, tBu), 58.3 (d, C-1), 119.3, 128.0,
128.9, 130.0, 134.5, 142.5 (5 d, s, C-2´, C-3´, Ph), 166.2 (s, C-1´), 196.4,
198.1 (2 s, C-2, C-3) ppm; IR (KBr):  = 3305 (NH), 2955–2875 (=C-H,
C-H), 1705–1685 (C=O), 1630 C=C) cm-1; HRMS: m/z [M + Na]+ calcd. for
C17H21NO3Na: 310.1414; found: 310.1422.
(E)-N-(2,2-Dimethyl-4,5-dioxohexan-3-yl)-3-(4-nitrophenyl)acrylamide
(3h): According to typical procedure 2, enamide 1h (200 mg, 0.69 mmol)
in trifluoroacetic acid (4 mL) gave 84 mg (55%) of 1,2-diketone 3h as pale
yellow solid. M. p. 132–134 °C; 1H NMR (500 MHz, CDCl3): δ = 0.99 ( s, 9
H, tBu), 2.36 (s, 3 H, Me), 5.35 (d, J = 7.6 Hz, 1 H, CH), 6.28 (dbr, J = 7.6
Hz, 1 H, NH), 6.37 (d, J = 15.5 Hz, 1 H, =CH), 7.49–7.62 (m, 3 H, Ar),
7.97–8.01 (m, 2 H, =CH, Ar) ppm; 13C NMR (125 MHz, CDCl3): δ = 23.5
(q, Me), 26.8, 35.1 (q, s, tBu), 58.3 (d, C-1), 124.8, 124.9, 129.2, 130.0,
130.9, 133.4, 137.4, 148.3 (6 d, 2 s, C-2´, C-3´, Ar), 164.8 (s, C-1´), 196.3,
198.1 (2 s, C-2, C-3) ppm; IR (KBr):  = 3295 (NH), 2965–2875 (=C-H,
C-H), 1710–1655 (C=O), 1615–1580 (C=C) cm-1; HRMS: m/z [M + Na]+
calcd. for C17H20N2O5Na: 355.1270; found: 355.1268.
Oxazole 2l and compound 5l: According to typical procedure 2, enamide
1l (75 mg, 0.219 mmol) in trifluoroacetic acid (2 mL) gave 6.5 mg (15%) of
oxazole 2l as a colorless solid and 5 mg (12%) of compound 5l as a pale
yellow oil. Data for oxazole 2l:[21] 1H NMR (500 MHz, CDCl3): δ = 2.51,
2.65 (2 s, 3 H each, Me), 7.44–7.48, 8.13-8.15 (2 m, 3 H, 2 H, Ph) ppm.
HRMS: m/z [M + H]+ calcd. for C16H12NO2: 202.0863; found: 202.0866.
Data for compound 5l: 1H NMR (500 MHz, CDCl3): δ = 1.41, 2.14 (2 s, 6 H
each, Me), 7.27–7.38, 7.67–7.69 (2 m, 6 H, 2 H, Ar), 8.05 (sbr, 2 H, NH)
ppm; 13C NMR (125 MHz, CDCl3): δ = 9.5, 23.8 (2 q, Me), 57.1 (s, C-1),
72.1 (s, C-3), 122.5, 124.4, 129.3, 129.7, 137.8, 139.1 (4 d, 2 s, Ar), 171.9
(s, C-1´), 199.9 (s, C-2) ppm; IR (neat):  = 3340 (NH), 3070–2980 (=C-H,
(E)-N-(2,2-Dimethyl-4,5-dioxohexan-3-yl)-3-(furan-2-yl)acrylamide
(3i): According to typical procedure 2, enamide 1i (50 mg, 0.13 mmol), in
trifluoroacetic acid (3 mL) gave 25 mg (70%) of 1,2-diketone 3i as pale
yellow oil. 1H NMR (400 MHz, CDCl3): δ = 0.97 (s, 9 H, tBu), 2.35 (s, 3 H,
MeCO), 5.33 (d, J = 7.4 Hz, 1 H, CH), 6.35 (d, J = 15.3 Hz, 1 H, =CH),
6.41–6.43 (m, 1 H, Furyl), 6.54 (d, J = 3.3 Hz, 1 H, Furyl), 7.35 (d, J = 15.3
Hz, 1 H, =CH), 7.41 (d, J = 3.1 Hz, 1 H, Furyl); 13C NMR (100 MHz, CDCl3):
δ = 23.5 (q, Me), 26.7, 35.1 (q, s, tBu), 58.3 (d, C-1), 112.3, 114.6 (2 d,
C-H), 1780, 1665 (C=O) cm-1; HRMS: m/z [M
C24H22N2O4Na: 425.1472; found: 425.1463.
+
Na]+ calcd. for
N-[2,2-Dimethyl-1-(3-methylquinoxalin-2-yl)propyl]acrylamide (6e),
Typical Procedure 3: 1,2-diketone 3e (66 mg, 0.31 mmol), o-
phenylenediamine (41 mg, 0.37 mmol), cerium(IV) ammonium nitrate (17
mg, 0.03 mmol) and water (2.5 mL) were stirred for 1 h at room
temperature. The mixture was quenched with ethyl acetate (2 mL) and
washed three times with water. The organic phase was dried with Na2SO4
and concentrated to dryness. The product was purified by column
chromatography (SiO2, hexanes/EtOAc 10%) furnishing 6e (45 mg, 51%)
C-3Furyl, C-4Furyl), 116.9, 128.9, 144.4, 151.0 (3 d, s, C-2´, C-3´, C-2Furyl
,
C-5Furyl), 166.2 (s, C-1´), 196.3, 198.0 (2 s, C-2, C-3) ppm; IR (neat):  =
3250 (NH), 2965–2880 (=CH, C-H), 1710–1660 (C=O), 1620–1530 (C=C)
9
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10.1002/ejoc.202000116
European Journal of Organic Chemistry
FULL PAPER
as a colorless solid. M. p. 131–134 °C; 1H NMR (400 MHz, CDCl3): δ =
1.00 (s, 9 H, tBu), 2.90 (s, 3 H, Me), 5.58–5.64 (m, 2 H, CH, =CH), 6.16–
6.31 (m, 2 H, =CH2), 6.88 (dbr, J = 9.4 Hz, 1 H, NH), 7.62–7.69 (m, 2 H,
Qin-H), 7.95–7.98 (m, 2 H, Qin-H) ppm; 13C NMR (100 MHz, CDCl3): δ =
23.5 (q, Me), 26.6, 37.8 (q, s, tBu), 56.0 (d, C-1), 126.8, 128.5, 128.7, 129.0,
129.7, 130.9, 140.4, 141.1, 153.0, 154.8 (t, 5 d, 4 s, C-2´, C-3´, Quin-C),
165.1 (s, C-1´) ppm; IR (KBr):  = 3290 (NH), 3070–2965 (=C-H, C-H),
(=C-H, C-H), 1680–1620 (C=O, C=C) cm-1; HRMS: m/z [M + H]+ calcd. for
C25H22N3O: 380.1763; found: 380.1756.
Crystal structure determination. X-ray single crystal diffraction of
compound 5j was performed on a Bruker AXS Smart CCD. The structures
were solved by direct methods, using SHELXS-97.[22] Refinement was
done with the least squares method (SHELXL Version2017/1).[22]
Molecular Graphics: ORTEP-3 for Windows. The CCDC number 1973331
contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1660–1650 (C=O, C=C) cm-1; HRMS: m/z [M
C17H24N3ONa: 306.1582; found: 306.1576.
+
Na]+ calcd. for
(E)-N-[2,2-Dimethyl-1-(3-methylquinoxalin-2-yl)propyl]but-2-enamide
(6f): According to typical procedure 3, a mixture of 1,2-diketone 3f (65 mg,
0.28 mmol) o-phenylenediamine (38 mg, 0.35 mmol) and ceric ammonium
nitrate (16 mg, .029 mmol) in water (3 mL) gave quinoxaline 6f (50 mg,
58%) as colorless solid. M. p. 154–156 °C; 1H NMR (400 MHz, CDCl3): δ
= 1.00 (s, 9 H, tBu), 1.81–1.83 (dd, J = 6.8, 1.7 Hz, Me), 2.90 (s, 3 H, Me),
5.58 (d, J = 9.5 Hz, 1 H, CH), 5.88–5.92 (dd, J = 15.2, 1.7 Hz, 1 H, =CH),
6.69 (dbr, J = 9.4 Hz,1 H, NH), 6.79–6.88 (m, 1 H, =CH), 7.64–7.69 (m, 2
H, Quin-H),7.96 (m, 2 H, Quin-H) ppm; 13C NMR (100 MHz, CDCl3): δ =
17.7 (q, Me), 23.6 (q, Me), 26.6, 37.7 (q, s, tBu), 55.8 (d, C-1), 125.1, 128.5,
128.7, 129.0, 129.7, 140.3, 140.4, 141.1, 153.0, 155.1 (6 d, 4 s, C-2´,
C-3´, Quin-H), 165.1 (s, C-1´) ppm; IR (KBr):  = 3285 (NH), 3060–2920
(=CH, C-H), 1665–1535 (C=O, C=C) cm-1; HRMS: m/z [M + Na]+ calcd. for
C18H23N3ONa: 320.1739; found: 320.1745.
Acknowledgements
Generous support of this work by the Deutsche
Forschungsgemeinschaft, the Alexander von Humboldt-Stiftung
and of Bayer Healthcare is gratefully acknowledged. We are very
thankful to Dr. Christian Mück-Lichtenfeld (Universität Münster)
for his support and for helpful discussions.
Keywords: Allenes • Density Functional Calculations • 1,2-
Diketones • Isoindenones • Reaction Mechanism • Quinoxalines
N-[2,2-Dimethyl-1-(3-methylquinoxalin-2-yl)propyl]cinnamamide
(6g): According to typical procedure 3, a mixture of 1,2-diketone 3g (75
mg, 0.26 mmol), o-phenylenediamine (33 mg, 0.31 mmol) and cerium(IV)
ammonium nitrate (14 mg, 0.025 mmol) in water (2.5 mL) gave quinoxaline
6g (50 mg, 53%) as a colorless solid. M. p. 176–178 °C; 1H NMR (400
MHz, CDCl3): δ = 1.05 (s, 9 H, tBu), 2.94 (s, 3 H, Me), 5.67 (d, J = 9.4 Hz,
1 H, CH), 6.73 (d, J = 15.6 Hz, 1 H, =CH), 6.94 (d, J = 9.4 Hz, 1 H, NH),
7.31–7.33, 7.47-7.49 (2 m, 3 H, 2 H, Ph), 7.63 (d, J = 15.6 Hz, 1 H, =CH),
7.67–7.70 (m, 2 H, Quin-H), 7.98–8.02 (m, 2 H, Quin-H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 23.6 (q, Me), 26.7, 37.8 (q, s, tBu), 56.1 (d, C-1),
120.7, 127.9, 128.5, 128.8, 129.1, 129.7, 134.8, 140.4, 141.1, 141.5, 153.1,
155.0 (8 d, 4 s, C-2´, C-3´, Ph, Quin-C), 165.5 (s, C-1´) ppm; IR (KBr):  =
3295 (NH), 3060–2870 (=C-H, C-H), 1660–1615 (C=O, C=C) cm-1; HRMS:
m/z [M + Na]+ calcd. for C23H25N3ONa: 382.1895; found: 382.1888.
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amide (6i): According to typical procedure 3, a mixture of 1,2-diketone 3i
(68 mg, 0.24 mmol), o-phenylenediamine (31.8 mg, 0.28 mmol) and ceric
ammonium nitrate (13 mg, 0.024 mmol) in water (2.5 mL) afforded
quinoxaline 6i (47 mg, 55%) as a brownish oil. 1H NMR (400 MHz, CDCl3):
δ = 1.03 (s, 9 H, tBu), 2.92 (s, 3 H, Me), 5.64 (d, J = 9.5 Hz, 1 H, CH),
6.39–6.43 (m, 2 H, =CH, Furyl-H), 6.50 (d, J = 3.2 Hz, 1 H, Furyl-H), 6.89
(d, J = 9.5 Hz, 1 H, NH), 7.38 (d, J = 15.2 Hz, 2 H, Fury-H, =CH), 7.64–
7.70 (m, 2 H, Quin-H),7.96-8.01 (m, 2 H, Quin-H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 23.6 (q, Me), 26.7, 37.8 (q, s, tBu), 56.1 (d, C-1), 112.2, 113.8,
118.5, 128.2, 128.5, 128.7, 128.0, 129.7, 140.0, 141.1, 144.0, 151.3, 153.3,
155.0 (9 d, 5 s, C-2´, C-3´, Furyl-C, Quin-H), 165.4 (s, C-1´) ppm; IR (neat):
 = 3295 (NH), 3050–2875 (=CH, C-H), 1670–1610 (C=O, C=C) cm-1;
HRMS: m/z [M + H]+ calcd. for C21H24N3O2: 350.1869; found: 350.1874.
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(6k):
According to typical procedure 3, a mixture of 1,2-diketone 3k (20 mg,
0.065 mmol), o-phenylenediamine (8.4 mg, 0.078 mmol) and cerium(IV)
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δ = 2.65 (s, 3 H, Me), 6.46 (d, J = 7.3 Hz, 1 H, CH), 6.59 (d, J = 15.6 Hz, 1
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11
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10.1002/ejoc.202000116
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Synthetic Methods
R. Kumar, M. K. Bera, R. Zimmer, D.
Lentz, H.-U. Reissig*, E.-U. Würthwein*
Page No. – Page No.
Alkoxyallene-Based LANCA Three-
Component Synthesis of 1,2-
Diketones, Quinoxalines and Unique
Isoindenone Dimers – A
Computational Study of the
Isoindenone Dimerization
Treatment with trifluoroacetic acid converted alkoxyallene-based β-alkoxy-β-
ketoenamides into 1,2-diketones (precursors of quinoxalines) or unexpectedly to
isoindenone dimers. The formation of these dimers is interpreted by DFT
calculations that support a stepwise process and disprove a concerted reaction.
12
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