The participation of 2H-pyran-2-ones in [4+2] cycloadditions: An experimental and computational study

Article abstract of DOI:10.1002/ejoc.201000236

Experimental and computational DFT studies of the Diels-Alder (DA) reaction mechanism for the series of 2H-pyran-2-ones 1 and non-symmetrically substituted alkynes 2, 10, and 11 were undertaken. Several 2H-pyran-2-ones 1 were treated with N,N-diethylpropy

Full text of DOI:10.1002/ejoc.201000236

FULL PAPER
DOI: 10.1002/ejoc.201000236
The Participation of 2H-Pyran-2-ones in [4+2] Cycloadditions:
An Experimental and Computational Study
[a][‡]
[a]
[b]
Andrej Perdih,[b][‡] Andrej Pevec, Tomaz Solmajer, and
ˇ
ˇ
ˇ
Bogdan Stefane,*
[a]
ˇ
Marijan Kocevar
Keywords: Cycloaddition / Density functional calculations / Donor-acceptor systems / Pyranones / Reaction mechanisms
Experimental and computational DFT studies of the Diels–
Alder (DA) reaction mechanism for the series of 2H-pyran-2-
ones 1 and non-symmetrically substituted alkynes 2, 10, and
amine (2) acts as a nucleophile reaction partner. The intro-
duction of electron-withdrawing carboxylic substituents on
the dienophiles 10 and 11 shifts the DA reaction with 2H-
pyran-2-ones to a less polar and more synchronous concerted
reaction mechanism. Calculated CT as well as values of the
global electrophilicity ω and nucleophilicity N indexes re-
vealed that 2H-pyran-2-ones act in this case as nucleophiles
and reacting dienophiles 10 and 11 as electrophiles. The re-
11 were undertaken. Several 2H-pyran-2-ones
1 were
treated with N,N-diethylpropynamine (2). The results point
toward a polar and asynchronous two-step mechanism that
is in line with the characteristics of a polar Diels–Alder (P-
DA) reaction mechanism.[5] Unexpected formation of minor
products 4a–d during the reaction of 1 with 2 can be rational- sults are consistent with the experimental data and kinetic
ized by considering the easily passable torsion barrier around
the newly formed C–C bond that enables two different cycli-
zation modes. The charge transfer (CT) and global reactivity
indices analyses demonstrated that in these reactions 2H-
pyran-2-ones act as electrophiles and N,N-diethylpropyn-
analyses, thus providing valuable insights into 2H-pyran-2-
one chemistry and paving the way for an efficient synthesis
of highly functionalized benzene derivatives as well as
broadening the mechanistic understanding of these highly
versatile reactions.
in the diene and electron-rich substituents on dienophile,
however, influence the reaction pathway. This effect could,
in general, be described by the frontier molecular orbital
(FMO) theory.[1a] Experimental data, however, suggest that
the picture is more complex.[6] Moreover, this type of sub-
stitution favors an asynchronous concerted mechanism[7]
which, in the limit scenario (the stabilization of charges),
becomes a stepwise mechanism with a large polar charac-
ter.[3]
There have been many reports on [4+2] cycloadditions of
2H-pyran-2-ones with a variety of dienophiles since they
were first described by Alder and Rickert[8] in 1937. The
electron-demand of the [4+2] process involving 2H-pyran-
2-ones as dienes depends highly on the structure of the di-
enophile. Electron-poor alkenes or alkynes react with 2H-
pyran-2-ones according to normal electron-demand pro-
cesses, whereas electron-rich dienophiles tend towards in-
verse electron-demand cycloadditions. For example, partici-
pation of enamines as dienophiles has been described to
proceed through an inverse electron-demand cycload-
dition,[7f] and cycloadditions involving ynamines are ex-
pected to proceed according to the same electron-demand
process. A further option is for the reaction to proceed
Introduction
The widely exploited Diels–Alder (DA) reaction repre-
sents an important synthetic methodology for the organic
chemist. The formation of DA cycloadducts can proceed
by different routes. Whereas most of the known reactions
proceed according to the rules of orbital symmetry,[1] step-
wise reactions involving biradicals,[2] zwitterionic as well as
dipolar intermediates[3] are also known. In recent years the
boundaries between the concerted and stepwise routes have
been intensively investigated.[4,5] For the DA reaction to
proceed reasonably fast, an acceptor (A) diene and a donor
(D) dienophile (inverse electron-demand reaction scenario)
or vice versa (normal electron-demand reaction scenario)
substitution pattern is required. Enhanced electrophilicity
[a] Faculty of Chemistry and Chemical technology,
University of Ljubljana
Asˇkercˇeva 5, 1000 Ljubljana, Slovenia
Fax: +386-1-2419 220
E-mail: bogdan.stefane@fkkt.uni-lj.si
[b] National Institute of Chemistry
Hajdrihova 19, 1001 Ljubljana, Slovenia
Fax: +386-1-4760 376
E-mail: andrej.perdih@ki.si
ˇ
[‡] Bogdan Stefane and Andrej Perdih contributed equally to this
either through
a two-stage asynchronous and polar
work.
(Michael-type intermediate) or synchronous concerted
(Scheme 1, path a) and non-polar transition state
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000236.
View this journal online at
wileyonlinelibrary.com
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Eur. J. Org. Chem. 2010, 5870–5883

[4+2] Cycloaddition of 2H-Pyran-2-ones
Scheme 1. Mechanistic alternatives for the DA reactions of 2H-pyran-2-ones as dienes with the non-symmetrically substituted internal
(R3 = Me, D = NEt2, or R3 = Me, A = CO2Et) and terminal (R3 = H, A = CO2Et) alkynes. In the case of a stepwise reaction (path a)
a zwitterionic intermediate formed from the electron poor (A substituent) substituted dienophile and the 2H-pyran-2-one is also possible.
(Scheme 1, path b),[5] to form the final products after subse- dition, producing a highly substituted benzene intermediate
quent retro-cycloaddition reaction with the loss of a CO2 with complete regioselectivity.[13] In all the mentioned ex-
molecule.
amples, little attention was paid to the high regioselectivity
More recently, the reactivity indices defined within the of the cycloaddition and no mechanistic aspects of these
conceptual DFT have been widely used to explain the polar transformations were explored. It was the aim of this study
Diels–Alder (P-DA) reactions.[5,9] Whereas the global elec- to also provide insights into this area.
trophilicity reported by Parr et al.[9a–9d] allows a unique
electrophilicity scale[9e] that explains the reactivity in P-DA
to be assembled,[5] the local electrophilicity index[9f] allows
the regioselectivity in these reactions to be explained
through the characterization of the most electrophilic center
of the reagents. Recently, Domingo et al. introduced simple
Results and Discussion
1. Experimental Study
During our investigation into the DA reactions of 2H-
global[9g] and local[9h] nucleophilicity indices, which enable pyran-2-one substrates containing a strong electron-donat-
an analysis of the behavior of the nucleophilic species.
ing or electron-deficient substituent at the 5-position, we
The purpose of this study was to contribute to a better observed a change in the reaction pathway from the normal
understanding of the features of the diene (2H-pyran-2-one) to the neutral or the inverse electron-demand scenario.[1c,1e]
and dienophile (alkyne derivative) responsible for the con- In due course, the reactions of 1 with N,N-diethylpropyna-
certed or stepwise reaction mechanisms of the DA cycload- mine (2) (Table 1) were performed in anhydrous tetra-
ditions. Here we report, for the first time, on mechanistic hydrofuran (THF) and dichloromethane solutions (by add-
studies of the cycloaddition reactions of N,N-diethylpropy- ing N,N-diethylpropynamine to a stirred solution of 1a–d,
namine (2), ethyl propiolate (10), and ethyl but-2-ynoate ca. 0.20 ) at 25 °C and under an argon atmosphere. The
(11) with a series of 2H-pyran-2-ones 1. Such a combina- reactions provided [4+2] cycloadducts in all cases. A careful
tion of an electron-rich dienophile (pyruvate enolate) and examination of the crude reaction mixtures using 1H NMR
an electron-deficient diene (5-acetyl-2H-pyran-2-ones) can spectroscopy showed that there were two products present.
also be found in nature, a manifest example being the bio- The structures of the products 3a–d (as the major products)
synthesis of macrophomate.[10] The work of other research- were confirmed by 2D NMR studies, where the C-3 and C-
ers[11a,11b] and our own experience with 2H-pyran-2-ones 4 methyl groups (being in the ortho position) show strong
and their fused derivatives have shown that they are very NOESY correlations. The bicyclic DA intermediates were
useful substrates for the DA reaction with alkenes[11a–11h] never observed but were further transformed into the final
and alkynes,[11a,11b,11f,11g] leading to the highly regioselec- products 3a–d after the loss of a CO2 molecule. The co-
tive formation of a variety of synthetically interesting pre- formed products were determined to be 4a–d (Scheme 2).[14]
cursors, including anilines and o-phenylenediamines. The formation of the rearranged 2H-pyran-2-ones 4a–d at-
Furthermore, it has been shown with two examples that tracted our attention and pointed to the possibility of a
N,N-diethylpropynamine (2) reacts with alkoxycarbonyl- stepwise mechanism.
substituted α-pyrones producing non-symmetrically substi-
Additionally, attempts to perform DA cycloadditions
tuted benzene derivatives as single isomers in good with 2H-pyran-2-ones lacking an electron-withdrawing
yields.[12] The same strategy was adapted by Ireland et al. group [such as 3-benzoylamino-5-(4-methoxyphenyl)-2H-
in their total synthesis of lasalocide A, in which they used pyran-2-one and 3-benzoylamino-2H-pyran-2-one] at the 5-
the synthetically more useful N,N-dibenzyl analogue of 2, position were unsuccessful and the corresponding cycload-
and showed that it does not alter the yields of the cycload- ducts could not be obtained. The fact that N,N-diethylpro-
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FULL PAPER
Table 1. [4+2] Cycloadditions of 2H-pyran-2-ones 1 with 2.
vent polarity was found to have only a moderate effect on
the product distribution (the ratio 3a:4a at 29 °C was 3.5:1
in CH2Cl2, 3:1 in THF, and 1.5:1 in acetonitrile). Similar
observations to ours were previously reported for DA reac-
tions involving polar intermediates.[3g] Additionally, the sol-
vent had only slight influence on the rate constants (the
disappearance of 1 following the second-order rate law): for
1a it is (1.20Ϯ0.04)ϫ10–3 in toluene, (4.3Ϯ0.5)ϫ10–3 in
acetonitrile, and (3.2Ϯ0.2)ϫ10–2 Lmol–1 s–1 in dimethyl
sulfoxide (DMSO) at 29 °C. We also varied the electronic
properties of 2H-pyran-2-ones by altering the substituent at
the 5-position from acetyl to benzoyl (e.g., 1b). Due to the
low solubility of the substrate 1b in THF and MeCN, the
kinetic measurements for 1b were performed in CHCl3 and
DMSO at 29 °C. The reaction of 1b with 2 is of a magni-
tude of 1.5 faster in DMSO [(9.1Ϯ0.2)ϫ10–3] than in
CHCl3 [(5.9Ϯ0.2)ϫ10–3]. Thus, the obtained kinetic data
suggest a moderate overall influence of the solvent on the
rates of the reaction.[1c] In contrast, when zwitterion forma-
tion seems to operate, acceleration effects of several powers
of ten were observed, for instance in cases of [2+2] cycload-
dition, if the polarity of the solvent is increased.[16,3a] How-
ever, in our case, the observed influence of the solvent on
the kinetics of the reaction cannot rule out a zwitterion
mechanism. Recent observations by Harrity and Gomez-
Bengoa et al. on the cycloaddition reactions of alkynylbo-
ronates support the kinetic results discussed above.[17]
Temperature-dependent measurements were then carried
out to determine the activation parameters for the reaction
Starting R1 R2
material
Solvent
Time [h]
Product [%][a]
3
4
3/4[b]
1
2
3
4
5
6
7
8
1a
1b
1c
Me NHCOMe CH2Cl2
THF
2.5
2.5
70
68
62
47
51
55
53
30
87[11f]
73
67
71
52
51
29
18
21
18
32
37
41
42
48
6
21
20
23
40
38
54
3.5:1
3:1
3:1
1.5:1
1.2:1
1:1
THF/H2O[c] 2.5
MeCN
Ph NHCOMe CH2Cl2
THF
2
2.5
2
2
2
THF/H2O[d]
1:1
MeOH
Me NHCOPh CH2Cl2
THF
1:1.5
7.5:1
3:1
3:1
3:1
1.5:1
1.5:1
1:2
9
10
11
12 1d
13
14
2.5
2.5
THF/H2O[d] 2.5
Ph NHCOPh CH2Cl2
THF
2.5
2.5
THF/H2O[c] 2.5
MeOH
15
2
[a] Average isolated yields after several runs are given. [b] Ratio 3:4
1
determined by H NMR analysis of the crude reaction mixture. [c]
THF/H2O = 2:1 (v/v). [d] THF/H2O = 5:1 (v/v).
Scheme 2. General reaction of the 2H-pyran-2-ones 1a–d with N,N-
diethylpropynamine (2).
pynamine (2) could be viewed as a nucleophilic reagent is of 1a–c with 2 in toluene and CHCl3. The corresponding
supported, for example, by its 13C NMR signal for the β- Eyring parameters are listed in Table 2.[14] In comparison
carbon atom having a resonance at a higher field (δ = with substrate 1a, a slightly lower activation enthalpy for
57.5 ppm) compared with alkylacetylenes (δ
= 70– the substrate 1b was observed, together with a slightly more
80 ppm),[15] the electron-deficient ethyl propiolate (δ = ordered rate-determining transition state (entry 2, Table 2).
74.8 ppm), and ethyl but-2-ynoate (δ = 84.9 ppm). This ob- Switching of the benzoyl and acetyl moieties at positions 3
servation is in agreement with the observation that reagent and 5 of 2H-pyran-2-one (substrates 1b and 1c, Table 2) did
2 appears to act as an inverse-electron-demand dienophile not have a major influence on the activation parameters.
in combination with the dienes 1a–d.
The relatively high negative value of the activation entropy,
Two mechanistic questions result from the formation of which is, however, close to the negative values observed in
the products 3 and 4: (1) Does the product 3 arise from a the concerted cycloadditions, does not necessarily rule out
concerted or stepwise (in borderline case involving a zwit- the involvement of a zwitterionic species. Namely, similar
terionic intermediate) mechanism? (2) Is the formation of values have also been observed for transition states with
the side product 4 a consequence of the relative ease of high-polarity.[18]
rotation around the first formed σ C–C bond in the step-
We turned, therefore, to trapping experiments to check
wise DA reaction followed by rearrangement of intermedi- the multi-step nature of the reaction. Despite many
ate 7 (see Scheme 4 below for full mechanistic details)? Al- attempts, we were not able to trap the putative zwitterionic
ternatively, 4 can be formed through intramolecular trap- intermediate using methanol as a solvent. Furthermore, the
ping of the zwitterionic intermediate formed by the initial reaction of 1b with 2 in the presence of either TMSCl (15
Michael reaction, which might also be the intermediate in fold excess) or a combination of TMSCl and (nBu)4NN3
the formation of 3. Zwitterionic intermediates, which are (15 fold excess) in anhydrous THF did not give any detect-
clear candidates in combinations of A-dienes–D-dieno- able side products that would indicate the formation of
philes or vice versa have been trapped in a few exam- putative zwitterions. When applying water as a co-solvent
ples.[3d–3h] However, only Sustmann et al. reported the isola- in THF (1:2, v/v), there was no change in the ratio of the
tion of zwitterions in a crystalline form.[6] In an effort to products 3:4 formed (Scheme 1). If water were to partici-
gain a better insight into the reaction mechanism, we per- pate in the reaction as a nucleophile it could be incorpo-
formed a detailed mechanistic investigation using the sub- rated into the product through a stepwise reaction mecha-
strates 1a–c. When polar intermediates are involved, one nism according to Scheme 3. When the experiment was con-
would expect a significant solvent effect. However, the sol- ducted with H218O/THF (1:2, v/v), under the same reaction
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[4+2] Cycloaddition of 2H-Pyran-2-ones
Table 2. Activation parameters for the reaction of 1a–1c with N,N-diethylpropynamine (2) and 1c and 1d with ethyl propiolate (10).
Reaction
R1
R2
Solvent
∆H‡ [kcalmol–1]
∆S‡ [calmol–1 K–1]
∆G‡ [kcalmol–1]
1a + 2
1b + 2
1c + 2
1c + 10
1d + 10
Me
Ph
Me
Me
Ph
NHCOMe
NHCOMe
NHCOPh
NHCOPh
NHCOPh
toluene
CHCl3
toluene
tetralin
tetralin
11.8Ϯ0.4
9.8Ϯ0.4
10.6Ϯ0.3
13.8Ϯ0.2
17.9Ϯ0.6
–34.0Ϯ1.4
–36.0Ϯ1.2
–35.5Ϯ0.9
–45.3Ϯ0.6
–34.4Ϯ1.2
22.0Ϯ1.4
20.6Ϯ1.2
21.2Ϯ1.0
27.3Ϯ0.6
28.2Ϯ1.3
Scheme 3. Possible reaction pathway for H218O incorporation in the stepwise reaction mechanism of 1 and 2.
conditions, no products incorporating 18O (as indicated by methoxyphenyl)-substituted 2H-pyran-2-one (1e) proved to
MS spectroscopy) as a result of external water trapping of be the most reactive substrate in combination with alkyne
the putative zwitterionic intermediate were observed.
10, whereas the 5-acetyl-substituted analogues were found
The stereochemistry of the double bond in the products to be the least reactive. To our surprise, we found that a
4 was determined by X-ray[14] analyses and a NOESY ex- slight change in the structure of the alkyne appears to sig-
periment to be cis in all cases. It appears that the configura- nificantly alter the reactivity. The reaction of 1c–g with
tion of the double bond in the products 4a–d probably orig- ethyl but-2-ynoate (11) was anticipated. Interestingly, when
inates from the bicyclic intermediate 7, which is derived the reaction was performed under the same conditions used
from the competing reaction pathway B presented in for the reaction of ethyl propiolate (10) or under harsher
Scheme 4, followed by a subsequent rearrangement reac- reaction conditions (200–230 °C in tetralin in a sealed
tion.
tube), no expected product was formed in the case of 1c,
Subsequently, we further examined the influence of a 1d, and 1f even after prolonged heating (for up to 96 h) of
change in the electronic properties of the acetylene dien- the reaction mixture. Instead, the starting material, con-
ophile. To this end, the reactivity of ethyl propiolate (10) taminated with some degradation products, was isolated.
and ethyl but-2-ynoate (11) dienophiles with 2H-pyran-2- On the other hand, the reaction of 1e and 1g with 11 was
one 1c–g was studied (Scheme 5). The reaction of 1c–g with productive after prolonged heating of the reaction mixture
the electron-deficient ethyl propiolate (10) was highly re- with six equivalents of alkyne at 200 °C,[14] resulting in non-
gioselective and required harsh reaction conditions, such as regioselective product formation. As shown in Scheme 5,
heating at 180 °C (heating to reflux in decalin) for several the cycloaddition of 1e and 1g gave the regioisomers 13e,
1
hours, to derive the trisubstituted benzene derivatives 12c– 14e and 13g, 14g. According to H NMR analysis of the
g in good yields[11f,11g] (Table 3). It was shown by Afarinkia crude reaction mixture, the ratios of the regioisomers were
et al. that 3- and 5-halo-2H-pyran-2-ones react with elec- 13e:14e, 3:1 and 13g:14g, 5:1, respectively.
tron-rich, electron-deficient and also electron-neutral al-
To rationalize the observed reactivity of 1 (Scheme 5), we
kenes in a very regio- and stereoselective way, whereas 4- studied the kinetics of the high-temperature reaction of 2H-
halo derivatives behave completely differently.[19] The 5-(4- pyran-2-one 1c and 1d with ethyl propiolate (10). The reac-
Eur. J. Org. Chem. 2010, 5870–5883
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FULL PAPER
Scheme 4. Pathways for the reaction of 2H-pyran-2-ones 1a–d with N,N-diethylpropynamine (2) with defined reaction energies. Path A
leads to the main product and path B leads to the side reaction product.
Table 3. [4+2] Cycloaddition of 2H-pyran-2-ones 1c–g with 10 and
11.
Starting material 1
Product 12
yield (%)
Product 13
yield (%)
Product 14
yield (%)
1c (R1 = COMe)
1d (R1 = COPh)
12c (94)
12d (66)
13c (n.r.)[a]
13d (n.r.)[a]
13e (44)
14c (n.r.)[a]
14d (n.r.)[a]
14e (17)
1e (R1 = 4-MeOC6H4) 12e (75)
1f (R1 = CO2Et)
1g (R1 = H)
12f (82)
12g (44)
13f (n.r.)[a]
13g (46)
14f (n.r.)[a]
14g (9)
[a] n.r.: no reaction.
Eyring plot[14] allowed us to establish a ∆S‡ value of
–45.3Ϯ0.6 calmol–1 K–1 (Table 2, reaction 1c + 10), which
is consistent with a highly ordered rate-determining transi-
tion state, suggesting a concerted 2H-pyran-2-one cycload-
dition reaction with alkynes and the absence of intermedi-
ates 5a presumed in the previous reactions involving the
formation of a single σ C–C bond. A significantly less nega-
Scheme 5. DA reaction of 2H-pyran-2-ones 1c and 1d with ethyl
propiolate (10) and ethyl but-2-ynoate (11) dienophiles at high tem-
perature. The reaction of 1g with 10 was performed in a sealed tube
in tetralin at 220 °C for 48 h.
tion could be simply followed by H NMR spectroscopic tive entropy value (∆S‡ = –34.8Ϯ1.2 calmol–1 K–1, Table 2
analysis of the crude samples. The experiments were con- and the Supporting Information) was observed for the ana-
ducted under pseudo-first-order reaction conditions across log 1d. The fact that the acetyl group presents less steric
a temperature range of 130–180 °C in tetralin. The kinetics hindrance for the transition state compared with the ben-
indicated that the reaction was pseudo-first-order with re- zoyl moiety in 1d is manifested in the larger enthalpy (∆H‡
spect to ethyl propiolate (10) under these conditions. An = 17.9Ϯ0.6 kcal/mol) of the rate-determining transition
1
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[4+2] Cycloaddition of 2H-Pyran-2-ones
state of 1d (Table 2). Both possible regioisomeric pathways zero-point energy (ZPE) corrections were computed at the
(A and B) for the reaction of 2H-pyran-2-ones 1a–d with corresponding DFT level of theory. The intrinsic reaction
ethyl propiolate (10) and ethyl but-2-ynoate (11) are pre- coordinate (IRC) paths were evaluated to examine the en-
sented in Scheme 6. To provide some insight into the ob- ergy changes of the intermediates, the transition states, and
served experimental results and to complement these find- the products of the reactions. The energies (enthalpies at
ings, we then turned to computational studies.
0 K) were determined relative to their optimized reaction
complex including the ZPE corrections:
∆H = ∆E + ∆ZPE
(1)
Because it is possible that the optimized reaction com-
plexes do not fully relate to the minima on the potential
energy surface, a careful examination of the optimized com-
plexes was performed. In all cases, the obtained complexes
were stable and converged to the optimized geometry.
Furthermore, differences in the relative energy were also de-
termined by taking the sum of both reactants as a starting
point. It was established that complex formation lowered
the relative energies by approximately 1 kcal/mol for the re-
actions of 1a+2 and 1b+2, and by approximately 6 kcal/mol
for the reactions 1c+10 and 1d+11 compared to the sum of
energies of the reactants (see Figure S3 of the Supporting
Information). Solvent effects were considered by B3LYP/6-
31+G(d) single-point calculations of previously obtained
gas-phase stationary points at 298 K using a self-consistent
reaction field (SCRF) based on the polarizable continuum
model of Tomasi et al.[24] The experimental solvents used
in kinetic studies: toluene (also used as an approximation
for tetralin), chloroform, and dimethyl sulfoxide (DMSO),
were modeled by the use of dielectric constants ε = 2.4, 4.9,
and 46.7, respectively.
The amount of charge transfer (CT) at the optimized
transition state structures was determined by using natural
population analysis. Additionally, reactivity indices were
computed to understand the reactivity of the molecules in
their ground state. These indices were introduced within the
DFT framework by Parr et al. and Pearson et al.[9] The
electronic chemical potential (µ) describes the changes in
the electronic energy with respect to the number of elec-
trons; the chemical hardness (η) and the global electrophi-
licity (ω), measure the stabilization in the energy when the
system acquires an additional electronic charge from the
environment. Recently, Domingo et al. introduced a nucleo-
philicity index (N), which allows the behavior of the nucleo-
philic species to be assessed.[9] The N-scale is the negative
value of the ionization potential calculated by Koopmans’
theorem with an arbitrary shifting of the origin. Equations
defining these indices are available in the Supporting Infor-
mation.
Scheme 6. Pathways for the reaction of 2H-pyran-2-ones 1c–g with
ethyl propiolate (10) and ethyl but-2-ynoate (11) (Path A and Path
B, two regioisomeric possibilities) with defined reaction energies.
For the reaction of 1c–e with 10, no regioisomeric alternative prod-
ucts 12c–g (regio) were isolated.
2. Computational Study
To support the experimental results and to gain insights
into the molecular mechanism of the [4+2] cycloaddition
reactions at the atomic level, a computational study of the
reactions between the dienes 1a–c and the non-symmetri-
cally substituted dienophiles 2, 10, and 11 was performed.
Previous theoretical studies on cycloadditions indicated
that the geometrical properties as well as the activation en-
ergies were in good agreement with the experimental acti-
vation energy values if the B3LYP hybrid functional[20] at
the density functional level of theory (DFT) was used for
the calculation.[21] Since it was expected that a negative
charge could be localized on the stationary points, the 6-
31+G(d) basis set was used because of its superior ability
to accommodate negative charges.[22] The geometry optimi-
zations for the reactants, intermediates, and transition states
were performed using the Gaussian03 program[23] and the
2.1. Reaction Energies and Analysis of the Optimized
Geometries
Figure 1 depicts the energy profile diagram for the reac-
Berny analytical gradient optimization method. The coordi- tion of 2H-pyran-2-one 1a with N,N-diethylpropynamine
nates of B3LYP 6-31+G(d)-optimized structures are avail- (2). The enthalpy differences are summarized in Table 4. An
able in the Supporting Information. The optimized station- analysis of the stationary points obtained for this cycload-
ary points were characterized by frequency calculations to dition can be summarized as follows: the rate-determining
ensure that the minima had zero imaginary frequencies and step of the reaction corresponds to nucleophilic attack of
that the transition states had one imaginary frequency. The the C-2 of the alkyne on the electrophilic center at C-6 of
Eur. J. Org. Chem. 2010, 5870–5883
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Figure 1. Schematic representation of the reaction coordinate for the cycloaddition of 2H-pyran-2-one 1a to N,N-diethylpropynamine
(2). Path A is depicted in black and path B in gray. The depicted values of ∆HA and ∆HB correspond to the reaction enthalpies
∆HA(1a+2) and ∆HB(1a+2) presented in Table 4.
the diene, affording the reaction intermediates (Me-5)A and
(Me-5)B by passing through the corresponding transition
states TSA(1a+2)1 and TSB(1a+2)1. The calculated poten-
tial energy barriers associated with these transition states
The conformational behavior of the intermediates (Me-
5)A and (Me-5)B was further investigated by constructing
the torsion potential for the rotation about the newly
formed σ C–C bond (Figure 3 and Scheme 4). The atoms
labeled 1–4 define the torsion angle. The computed confor-
mational dependence for a rotation about the newly formed
C–C bond is presented in Figure 3 (conformations at 15,
30, 45, and 60°). The intermediates (Me-5)A (99.57°) and
(Me-5)B (5.27°) (Scheme 4) are separated by a small rota-
tional energy barrier, indicating that these two conforma-
tional states can easily equilibrate before proceeding to the
next cyclization step (see Table S5 of the Supporting Infor-
mation for exact energy values).
Following formation of the first σ C–C bond, the second
cyclization step proceeds via the transition states
TSA(1a+2)2 and TSB(1a+2)2, resulting in the intermediate
compounds Me-6 and Me-7. The obtained values for the
unique imaginary frequencies suggest a very flat potential
energy surface around the transition state structures and
the low calculated activation barriers correlate nicely with
analogous ring-closing transitions studied previously.[25] We
cannot exclude the possibility that the low imaginary fre-
quency is associated with rotation of one of the methyl
groups. The resulting energy barrier of the transition struc-
ture ∆H‡B(1a+2)2 is 1.3 kcal/mol higher than the barrier to
∆H‡A(1a+2)2, indicating the favorable cyclization step of
the latter, yielding the Me-6 reaction intermediate. The ex-
perimentally determined product distribution of the final
products 3a:4a was 3.5:1 (Table 1); the calculated barrier
thus corresponded nicely to a theoretical value of approxi-
mately 0.8 kcal/mol. Nevertheless, a caveat should be added
that for a precise evaluation of product distribution, higher
levels of quantum theory would be necessary. The transition
state TSA(1a+2)3 is associated with the loss of a CO2 mole-
cule, which ultimately affords the main product 3a. This
are located at ∆H‡A(1a+2)1
=
19.0 kcal/mol and
∆H‡B(1a+2)1 = 17.1 kcal/mol, respectively. Two possible
positions of the dienophile 2 relative to the diene 1a (geom-
etry A and B in Scheme 4) were investigated to better model
the second cyclization step of the reaction yielding either
Me-6 (path A, main product 3a formation) or Me-7 (path
B, side product 4a formation) chemical species.
Table 4. Calculated relative energies for the stationary points of the
cycloaddition of 2H-pyran-2-one 1a and N,N-diethylpropynamine
(2).[a]
∆Hrel. [kcal/mol]*
∆Hrel. [kcal/mol]
∆H‡A(1a+2)1
∆HA(1a+2)1
∆H‡A(1a+2)2
∆HA(1a+2)2
∆H‡A(1a+2)3
∆HA(1a+2)3
19.0
12.3
13.9
–8.2
–0.3
–58.7
∆H‡B(1a+2)1
∆HB(1a+2)1
∆H‡B(1a+2)2
∆HB(1a+2)2
∆H‡B(1a+2)3
∆HB(1a+2)3
∆H‡B(1a+2)4
∆HB(1a+2)4
∆H‡B(1a+2)5
∆HB(1a+2)5
17.1
13.2
15.2
–22.0
–10.6
–12.1
–12.1
–26.7
–17.0
–41.5
[a] All energies were calculated at the B3LYP/6-31+G(d) level, with
zero point energy corrections.[4a,25]
The B3LYP/6-31+G(d)-optimized geometries of the tran-
sition states TSA(1a+2)1 and TSB(1a+2)1 are depicted in
Figure 2. The level of synchronicity was measured by the
difference in the length of the two σ-bonds formed during
the cyclization process. The difference between the bond-
forming lengths in TSA(1a+2)1 (1.9 Å) and TSB(1a+2)1
(1.5 Å) arises from the highly asynchronous cycloaddition
reaction.[4a,21]
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[4+2] Cycloaddition of 2H-Pyran-2-ones
Figure 2. Optimized transition state structures TSA(1a+2)1 and TSB(1a+2)1 for the first step of the Diels–Alder reaction of 2H-pyran-
2-one 1a and N,N-diethylpropynamine (2). The values of the lengths of the bonds directly involved in the reaction were obtained at the
B3LYP/6-31+G(d) level and are given in Ångstrøms [Å]. Two geometries (path A and path B) leading to the reaction products 3a and
4a, respectively, were considered.
The cycloaddition of 2H-pyran-2-one 1b and N,N-di-
ethylpropynamine (2) (Table 5) was computationally investi-
gated up to the formation of the second σ C–C bond, af-
fording Ph-6 and Ph-7, because in the 1a+2 cycloaddition
the initial reaction steps were found to be rate-determining.
As in the case of 1a+2, two possible positions of the dien-
ophile 2 relative to the diene 1b were investigated: Path A,
which ultimately leads to the main reaction product 3b, and
Path B, which affords the side product 4b. The reaction en-
ergy profile of the phenyl-substituted compounds is avail-
able as Figure S4 of the Supporting Information. The en-
thalpy change ∆H‡B(1b+2)1, which is associated with for-
mation of the transition state structure TSB(1b+2)1, was
calculated to possess a 0.9 kcal/mol lower relative potential
energy barrier [∆H‡B(1b+2)1 = 17.0 kcal/mol] than its
counterpart transition state structure TSA(1b+2)1. In Fig-
Figure 3. Cycloaddition of 2H-pyran-2-one 1a and N,N-diethylpro-
ure 4, B3LYP/6-31+G(d)-optimized geometries of the tran-
pynamine (2). The intermediates (Me-5)B and (Me-5)A (boundary
sition states TSA(1b+2)1 and TSB(1b+2)1 are depicted. The
structures) and the computed torsional potential for the rotation
bond lengths in the first transition state once more show a
(in steps of 15°) about the newly formed σ C–C bond in the inter-
mediate is shown (Scheme 4). The atoms labeled 1–4 define the high level of asynchronicity in this DA cycloaddition reac-
tion.[4a,21] The lengths of the forming bonds for the two
torsion angle. The geometry of the intermediate structure at a tor-
sion angle of 45° is shown. The relative energy values were scaled
possible transition state geometries were about 1.7 Å and
from the value at torsion potential of 5.27°. This torsion angle
1.4 Å. The intermediates (Ph-5)A and (Ph-5)B are energeti-
corresponds to the (Me-5)B intermediate.
cally separated by a small barrier of 0.2 kcal/mol. The en-
ergy barrier associated with the transition structure
TSB(1b+2)2 is 2.1 kcal/mol higher than that calculated for
reaction was found to be a very exothermic process, with
an energy change of –58.7 kcal/mol compared to the initial
reaction complex. The rearrangement leading to the side
product 4a begins with the ring-opening of the Me-7 pyr-
anone moiety [TSB(1a+2)3 transition state], yielding the in-
Table 5. Calculated relative energies of the cycloaddition of Ph-2H-
pyran-2-one (1b) and N,N-diethylpropynamine (2).[a]
termediate Me-8 (Scheme 4 and Table 4). Subsequently, the (A)
∆Hrel. [kcal/mol] (B)
∆Hrel. [kcal/mol]
∆H‡A(1b+2)1
∆HA(1b+2)1
∆H‡A(1b+2)2
∆HA(1b+2)2
17.9
11.8
11.8
–9.4
∆H‡B(1b+2)1
∆HB(1b+2)1
∆H‡B(1b+2)2
∆HB(1b+2)2
17.0
12.2
13.9
formation of the side product 4a proceeds in two steps: In
the first step a new bond is formed between the Me-8 carb-
oxylic oxygen and a carbon atom adjacent to the oxygen of
the pyran moiety [TSB(1a+2)4 transition state] giving a new
bicyclic Me-9 structure. Finally, after ring-opening of the
Me-9 pyran ring [TSB(1a+2)5 transition state, see
Scheme 4] the side product 4a is obtained, which was found
to be 41.5 kcal/mol lower on the energy scale compared
with the starting reaction complex.
[b]
–22.3
[a] All energies were calculated at the B3LYP/6-31+G(d) level with
zero point energy corrections.[4a,25] [b] All attempts to locate the
ring-closing transition structure proceeding from the intermediate
(Ph-5)B were unsuccessful, thus this energy is approximated with
the optimized TSB(1b+2)2 structure with no imaginary fre-
quency.[25]
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Figure 4. Optimized transition state structures TSA(1b+2)1 and TSB(1b+2)1 for the DA reaction of 2H-pyran-2-one (1b) and N,N-
diethylpropynamine (2). The lengths of the bonds directly involved in the reaction obtained at the B3LYP/6-31+G(d) level in toluene are
given in angstroms [Å]. Two conformations (Paths A and B) leading to the reaction products 3b and 4b, respectively, were considered.
TSA(1b+2)2, indicating (as in the previous case of 1a+2) sition state TSA(1c+10) for the reaction of diene 1c with
that the DA reaction favors the cyclization step leading to 10. This finding suggests a much higher level of synchron-
formation of the main product. This is in line with the ob- icity, and consequently a much more concerted reaction
tained experimental product ratio 3b:4b of 1.2:1 (Table 1).
pathway leading to the formation of the two σ C–C bonds
Investigations into the reaction of 2H-pyran-2-one deriv- compared to the reactions of 1a+2 and 1b+2 discussed
ative 1c with ethyl propiolate (10) and ethyl but-2-ynoate above. The results are consistent with the experimental find-
(11) provided two transition state structures that were sig- ing of a large, negative value for the activation entropy
nificantly different from the transition states discussed (–45.3Ϯ0.6 calmol–1 K–1) for the reaction pair 1c+10. A
above. The optimized geometries of the transition states as similar conclusion regarding the synchronicity of the DA
well as their regioisomeric counterparts are depicted in Fig- reaction can be obtained for the reaction of diene 1c with
ure 5. It can be readily observed that the calculated differ- ethyl but-2-ynoate (11), in which the difference in the bond
ence in the partial bond lengths is only 0.79 Å for the tran- lengths (∆r) is 0.47 Å. Notably, no intermediate structures
Figure 5. Transition state structures for the reaction of 2H-pyran-2-one 1c with (a) ethyl propiolate (10) (left) and (b) ethyl but-2-ynoate
(11) (right). The lengths of the bonds directly involved in the reaction were obtained at the B3LYP/6-31+G(d) level and are given in
angstroms [Å].
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[4+2] Cycloaddition of 2H-Pyran-2-ones
similar to those modeled in the previous reactions with di-
enophile 2 [e.g., (Me-5)A, (Me-5)B and (Ph-5)A, (Ph-5)B]
with a single C–C bond formed, could be obtained compu-
tationally, which lends support to a highly concerted reac-
tion pathway. The calculated differences in the activation
enthalpies for paths A and B in the reactions of 1a or 1b
with 2 are smaller (by 6–8 kcal/mol) than those calculated
for the addition of ethyl propiolate (10) and ethyl but-2-
ynoate (11) to pyranone 1c (Table 6). This finding is re-
flected in the harsh experimental reaction conditions and
prolonged heating necessary to accomplish product forma-
tion in the reactions 1c+10 or 11 compared with the pre-
vious reactions. Figure 6 depicts the energy diagram for the
reaction of 2H-pyran-2-one 1a with ethyl propiolate (10).
In terms of the regioselectivity of the 1c+10 reaction, the
formation of the TSA(1c+10)1 is favored over its re-
gioisomer TSA(1c+10)2 by about 4 kcal/mol. Higher acti-
vation enthalpy values (31–33 kcal/mol) were obtained for
the reaction of 1c with 11. Unfortunately, because all
attempts to isolate the product were unsuccessful, the re-
gioselectivity cannot be directly compared to the experi-
mental results for this reaction. However, the lower differ-
ence in the activation energy and the fact that pyranones 1e
and 1g successfully reacted nonregioselectively with 11 after
prolonged heating under harsh reactions conditions at
200 °C, renders the reaction of ethyl but-2-ynoate (11) with
pyranones potentially less regioselective.
Figure 6. Schematic representation of the reaction coordinate for
the cycloaddition of 2H-pyran-2-ones 1c to ethyl propiolate (10).
Path A is depicted in black and the regioalternative path B in gray.
The depicted values of ∆HA and ∆HB correspond to the reaction
enthalpies ∆HA(1c+10) and ∆HB(1c+10) presented in Table 6.
2.2. Global Reactivity Indices and Charge-Distribution
Analysis
The stationary points of the four studied DA reactions
were further analyzed and the amount of charge transfer
(CT) at the optimized transition states,[26,27] as well as
global reactivity indices defined in the context of the DFT
theory,[9] were calculated (see Tables S6–S7 and Tables S14–
15 of the Supporting Information). In addition, the nucleo-
philicity index (N), which allows the behavior of the nucleo-
philic species to be assessed, was determined.[9] Representa-
tive data are presented in Table 7.
The amount of charge transferred during transition state
formation was determined by natural population analysis
(Tables S8–S11 and S16–19 of the Supporting Information).
In the reaction of 1a with 2, the values of charge [0.43 au
(path A) and 0.45 au (path B)] transferred from 2 to 1a
suggest a polar reaction pathway for the reaction. We would
also like to note that the relatively large charge transfer and
high non-symmetry of the C–C bond formation in the reac-
tion of 1 with 2 might even support an ionic character for
Table 6. Calculated relative energies of the cycloaddition between
the 2H-pyran-2-one 1c and the ethyl propiolate (10) (left) and the
ethyl but-2-ynoate (11) (right), respectively. (A) and (B) denote two
possible orientations of the reactants in the initial complex deriving
two regioisomers.[a]
(A)
∆Hrel. [kcal/mol]
∆Hrel. [kcal/mol]
∆H‡A(1c+10)1
∆HA(1c+10)1
∆H‡A(1c+10)2
∆HA(1c+10)2
25.4
–18.0
–8.8
∆H‡A(1c+11)1
∆HA(1c+11)1
∆H‡A(1c+11)2
∆HA(1c+11)2
33.0
–8.1
–1.1
–76.5
–61.7
(B)
∆Hrel. [kcal/mol]
∆Hrel. [kcal/mol]
∆H‡B(1c+10)1
∆HB(1c+10)1
∆H‡B(1c+10)2
∆HB(1c+10)2
29.47
–17.91
–10.16
–69.75
∆H‡B(1c+11)1
∆HB(1c+11)1
∆H‡B(1c+11)2
∆HB(1c+11)2
31.02
–10.71
–2.56
–58.42
[a] All energies were calculated at the B3LYP/6-31+G(d) level with
zero point energy corrections.[4a,25]
In addition to the results of the analysis of the energy these reactions. As expected, the comparable reaction of
changes along the reaction coordinates, the calculated en- 1b+2 showed similar behavior [0.42 au (path A) and 0.44 au
thalpy differences, corrected by the zero-point energy (∆H), (path B)] for the charge transfer from 2 to 1b. Furthermore,
were supplemented with solvent effects, which were studied inclusion of solvent effects had only marginal effects on the
by using the polarizable continuum method[24] (Tables S3, CT values, thus complementing nicely the observed minor
S5, S12, and S13 of the Supporting Information). In gene- influence of the solvent on the observed rate constants. The
ral, the inclusion of a solvent contribution lowers the free large observed CT of 0.42–0.45 au for the neutral species
energy of the transition states by 3–5 kcal/mol. This is rea- entering the reaction is in line with the P-DA reaction.[5]
sonably close to the values of 2–3 kcal/mol found previously On the other hand, the values of CT in the reverse direc-
by Domingo et al., in the cycloaddition of 1,3-butadienes tion, from the pyranone 1c to the substituted carboxylate
with dimethyl acetylenecarboxylate,[21k] and is in line with dienophiles 10 and 11, are considerably lower (0.05 au and
the limited influence of the solvent on the reaction rates 0.04 au).[5] These values exemplify the significant change in
observed experimentally.
the polar character of the latter adduct.
Eur. J. Org. Chem. 2010, 5870–5883
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FULL PAPER
Table 7. Global reactivity indices of the reactants[a] involved in the cycloaddition reactions of 2H-pyran-2-ones 1a–f with the non-symmet-
rically substituted alkynes 2, 10, and 11.
Compound
µ [au]
η [au]
∆Nmax
ω [eV]
N[b]
Ethyl propiolate (10)
2H-Pyran-2one (1b)
2H-Pyran-2one (1a)
2H-Pyran-2-one (1c)
2H-Pyran-2-one (1d)
2H-Pyran-2-one (1f)
2H-Pyran-2-one (1g)
2H-Pyran-2-one (1e)
Ethyl but-2-ynoate (11)
1-(Diethylamino)propyne (2)
Ϫ0.1756
Ϫ0.1599
Ϫ0.1606
Ϫ0.1589
Ϫ0.1593
Ϫ0.1561
Ϫ0.1507
Ϫ0.1447
Ϫ0.1605
Ϫ0.0952
0.1509
0.1501
0.1586
0.1554
0.1470
0.1558
0.1528
0.1455
0.2294
0.1988
1.1637
1.0653
1.0126
1.0221
1.0837
1.0019
0.9862
0.9945
0.6997
0.4789
2.78
2.32
2.21
2.21
2.35
2.12
1.98
1.96
1.53
0.62
1.46
3.01
2.88
2.97
3.07
3.04
3.23
3.49
1.91
4.11
[a] Global electrophilicity (ω); electronic chemical potential (µ) and chemical hardness (η); ∆Nmax maximal amount of electronic charge
that the electrophile can accept, and the nucleophilicity index (N). [b] The HOMO energy of tetracyanoethylene (TCE) is –0.34577 au
at the same level of theory.[9]
The calculated electronic characteristics can also be previously observed behavior. N,N-Diethylpropynamine (2)
correlated with the measured, as well as calculated, acti- has a larger nucleophilic index (N = 4.11 eV) compared
vation parameters. Reactions with lower CT, for example, with the reacting pyranones 1a–d (N = 2.88–3.07 eV), which
reaction of pyranone 1c with 10, correlated with the experi- renders this species nucleophilic in the polar DA reactions.
mentally and computationally observed higher energy bar- On the other hand, the reverse situation is observed for the
riers necessary for this DA reaction to occur. In contrast, reaction of 1c (N = 2.97 eV) with compounds 10 (N =
higher CT values for the 1a+2 and 1b+2 reactions corre- 1.46 eV) and 11 (N = 1.97 eV), in which the pyranones act
sponded to a lower activation energy barrier. This also leads as nucleophiles. Due to the smaller difference in the N in-
to a change in the reaction mechanism and suggests that a dex, a less polar character is displayed for the 1c+10 reac-
significantly more polar reaction takes place in the latter tion.
cases.[5]
The electronic chemical potential µ of the dienes 1a–d
(–0.1606, –0.1599, –0.1589, and 0.1593 au, respectively) is
lower than those of ynamine 2 (–0.0952 au), indicating that
Conclusions
CT will take place during cycloaddition from the ynamine
The molecular mechanisms for [4+2] cycloaddition reac-
2 to the dienes 1a–d. On the other hand, the electronic tions involving a combination of acetylene derivatives and
chemical potential of the electron-deficient acetylenes 10 2H-pyran-2-ones have been studied by a combination of ex-
(–0.1756 au) is lower than that of the dienes. Thus, for the perimental and computational DFT methods. Our theoreti-
DA reaction between 10 and the dienes 1c and 1d, there is cal and experimental investigations revealed the polar char-
a clear reversal in the flow of the CT going from the dienes acter of the DA reaction between N,N-diethylpropynamine
to acetylene derivative 10, which possesses the lowest chem- (2) and 2H-pyran-2-ones 1. These reactions are described
ical potential value of the series.
by an asynchronous, two-step mechanism characterized by
A low value of global electrophilicity (ω = 0.62 eV) for the rate-limiting nucleophilic attack, Michael addition, of
compound 2 classifies this species as a marginal electro- the alkyne 2 to the electron-deficient 2H-pyran-2-one deriv-
phile. On the other hand, a relatively high value of ω calcu- atives 1 with the formation of a C–C bond. This is in line
lated for pyranone dienes (ω = 1.96–2,32 eV) puts these with the characteristics of a P-DA reaction mechanism.[5]
chemical species among the moderate electrophiles on the Ring closure affords the final cycloadduct through the for-
electrophilicity scale for common substrates involved in the mation of the second C–C bond in the subsequent stage of
DA reactions.[5] In comparison to the electrophilicity of 1a the reaction. The higher CT and global reactivity indices
and 1b, the difference ∆ω = 1.59 eV and 1.7 eV confirms confirmed the polar nature of the reaction and identified
the flow of the electrons from compound 2 to the pyranone, ynamine 2 as a nucleophilic species in these polar DA reac-
as well as the polar nature of these types of reaction.[5] This tions. The observed mechanism has parallels in the stepwise
can be further correlated with the experimental observation mechanism studied by Jorgensen et al. in the enzymatic en-
from 13C NMR spectroscopy (see above), which supports vironment of the macrophomate synthase, where evidence
the notion that 2 acts as a nucleophile in the reaction with was presented that the Diels–Alder transition state is less
dienes 1a and 1b. Similarly, compound 10, which possesses stable than the Michael-aldol transition state,[10c] as well as
a greater global electrophilicity index (ω = 2.78 eV) com- in recent examples of the competition between a polar Di-
pared with 2H-pyran-2-ones, results in a reverse flow of els–Alder and a two-step reaction described by Bongini and
electrons during the reaction. The smaller difference with Panunzio et al.[28] The unexpected formation of the minor
1c (∆ω = 0.57 eV) is in accordance with the lower polar products 4a–d during the reaction of 1 with 2 can be ration-
character of this DA reaction. In addition, analysis of the alized by considering the low torsion barrier around the
nucleophilicity index[9] N showed that it was in line with the newly formed C–C bond, which enables two different cycli-
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[4+2] Cycloaddition of 2H-Pyran-2-ones
zation modes. Singleton et al.[29] have employed a dynamic
trajectory approach[30] to point out the possibility of non-
statistical recrossing to explain the yield of minor products.
The change in the electrostatic nature of the acetylene
derivatives to the carboxyl-substituted chemical species 10
and 11 resulted in a change in the reaction pathway, with
2H-pyran-2-ones 1 displaying a more synchronous, con-
certed pathway. Furthermore, a smaller CT in the reverse
direction to the previous reaction, a lower difference in the
global electrophilicity ω and nucleophilicity index N, fa-
vored a less polar and more energy-demanding reaction
pathway. In these DA reactions, 2H-pyran-2-ones 1 played
the role of the nucleophile. Overall, all the computational
results consistently corroborated the available experimental
data and kinetic analyses. We believe that the results of this
study will assist in the identification of compatible diene–
dienophile substrates for use in 2H-pyran-2-one chemistry
that will enable efficient cycloaddition reactions to be devel-
mixture of the starting 2H-pyran-2-one 1c–g (2 mmol) and dien-
ophile 10 or 11 (12 mmol) in decaline or tetraline (6 mL) was
heated at 160–195 °C for 6–48 h. After the reaction was completed,
the volatile material was evaporated under high vacuum and the
residue was purified by column chromatography on SiO2.
Ethyl 2-Benzamido-5-methylbenzoate (12g): After purification by
column chromatography (EtOAc/petroleum ether, 1:5 then 1:3),
white crystals of 12g were obtained; yield 180 mg (44%); m.p.
151.5–152.5 °C (CH Cl /petroleum ether). IR (KBr): ν = 3445,
˜
2
2
1749, 1634, 1515, 1294, 1248, 1090, 989 cm–1. 1H NMR (300 MHz):
δ = 1.42 (t, J = 7.0 Hz, 3 H, Et), 2.35 (s, 3 H, Me), 4.40 (q, J =
7.0 Hz, 2 H, Et), 7.40 (dd, J = 8.5, 2.0 Hz, 1 H, Ph), 7.47–7.56 (m,
3 H, Ph), 7.88 (d, J = 2.0 Hz, 1 H, Ph), 8.02–8.05 (m, 2 H, Ph),
8.81 (d, J = 8.5 Hz, 1 H, NH) ppm. 13C NMR (75.5 MHz): δ =
14.2, 20.7, 61.4, 115.3, 120.4, 127.3, 128.7, 130.9, 131.7, 132,0,
135.0, 135.3, 139.5, 165.4, 168.6 ppm. MS (ES+): m/z = 284 [M
+ H]+. HRMS: calcd. for C17H18NO3: 284.1287; found 284.1285.
C17H17NO3 (283.33): calcd. C 72.071, H 6.05, N 4.94; found C
71.95, H 6.01, N 5.01.
oped and lead to highly functionalized benzene derivatives. Ethyl 5-Benzamido-4Ј-methoxy-2,3-dimethylbiphenyl-4-carboxylate
(13e): After purification by column chromatography (EtOAc/petro-
leum ether, 1:5 then 1:3), white crystals of 13e were obtained; yield
180 mg (44%); m.p. 151.5–152.5 °C (Et2O/petroleum ether). IR
The results should also contribute to a deeper mechanistic
understanding of these highly versatile reactions.
(KBr): ν = 3437 (brw), 1724 (s), 1639 (s), 1611 (m), 1512 (s), 1459
˜
(m), 1292 (m), 1246 (s), 1192 (m), 1108 (m), 1039 (s), 831 (s), 692
1
(s) cm–1. H NMR (300 MHz): δ = 1.40 (t, J = 7.0 Hz, 3 H, Et),
Experimental Section
2.17 (s, 3 H, Me), 2.25 (s, 3 H, Me), 3.83 (s, 3 H, Me), 4.42 (q, J
= 7.0 Hz, 2 H, Et), 6.91 (AAЈXXЈ, J = 8.5 Hz, 2 H, pMeOAr), 7.20
(AAЈXXЈ, J = 8.5 Hz, 2 H, pMeOAr), 7.44–7.56 (m, 3 H, Ph), 7.68
(s, 1 H, Ph), 7.77 (br. s, 1 H, NH), 7.85–7.88 (m, 2 H, Ph) ppm.
13C NMR (75.5 MHz): δ = 14.2, 14.7, 17.3, 55.3, 61.2, 113.5, 126.0,
126.7, 127.1, 128.8, 129.3, 130.4, 131.9, 133.1, 133.4, 134.6, 136.4,
140.7, 158.7, 165.8, 170.1 ppm. MS (ES+): m/z = 404 [M + H]+.
HRMS: calcd. for C25H26NO4: 404.1862; found 404.1866.
General Procedure for the Cycloaddition of 2H-Pyran-2-ones 1a–c
with N,N-Diethyl-1-propyn-1-amine: To a solution of one of the 2H-
pyran-2-ones 1a–c (1 mmol) in THF (5 mL), N,N-diethylpropyn-
amine (222 mg, 2 mmol) was added. The reaction mixture was
stirred at r.t. for 0.75–2.5 h and then evaporated to dryness. Purifi-
cation of the residue by column chromatography (light petroleum/
ethyl acetate, 5:3 then 1:1) gave the products 3a–c. Additionally,
4a–c were isolated as white solids.
Ethyl 5-Benzamido-4Ј-methoxy-2,4-dimethylbiphenyl-3-carboxylate
(14e): After purification by column chromatography (EtOAc/petro-
leum ether, 1:5 then 1:3), white crystals of 14e were obtained; yield
70 mg (17%); m.p. 137.5–138.5 °C (Et2O/petroleum ether). IR
N-[5-Acetyl-2-(diethylamino)-3,4-dimethylphenyl]acetamide
Yield 68%; yellow oil. IR (NaCl): ν = 3318 (br), 2969 (m), 1686
(3a):
˜
(s), 1574 (s), 1507 (s), 1409 (m), 1322 (m), 1268 (m), 1216 (m), 1188
1
(m), 888 (w) cm–1. H NMR (300 MHz): δ = 1.03 (t, J = 7.0 Hz, 6
(KBr): ν = 3451 (br., w), 1669 (s), 1579 (s), 1509 (s), 1405 (m), 1283
˜
(s), 1246 (s), 1176 (m), 1138 (m), 836 (m), 697 (m) cm–1. H NMR
1
H, Et), 2.19 (s, 6 H, Me), 2.27 (s, 3 H, Me), 2.57 (s, 3 H, Me),
3.00–3.08 (m, 2 H, Et), 3.15–3.22 (m, 2 H, Et), 8.61 (s, 1 H, Ph),
9.17 (br. s, 1 H, NH) ppm. 13C NMR (75.5 MHz): δ = 14.8, 15.5,
16.1, 24.7, 30.1, 48.3, 115.2, 130.8, 135.7, 137.5, 137.6, 137.9, 167.7,
203.4 ppm. MS (EI, 70 eV): m/z (%) = 276 (100) [M]+, 261 (50),
247 (55), 205 (90), 189 (53). HRMS: calcd. for C16H24N2O2:
276.1838; found 276.1845.
(300 MHz): δ = 1.41 (t, J = 7.0 Hz, 3 H, Et), 2.18 (s, 3 H, Me),
2.41 (s, 3 H, Me), 3.85 (s, 3 H, Me), 4.45 (q, J = 7.0 Hz, 2 H, Et),
6.94 (AAЈXXЈ, J = 8.5 Hz, 2 H, pMeOAr), 7.26 (AAЈXXЈ, J =
8.5 Hz, 2 H, pMeOAr), 7.46–7.56 (m, 3 H, Ph), 7.91–7.93 (m, 2 H,
Ph), 8.25 (s, 1 H, Ph), 9.87 (br. s, 1 H, NH) ppm. 13C NMR
(75.5 MHz): δ = 14.1, 17.3, 19.0, 55.3, 61.7, 113.5, 121.2, 121.3,
127.1, 128.8, 130.4, 131.1, 131.8, 134.1, 134.4, 134.8, 136.9, 145.3,
158.8, 165.0, 169.8 ppm. MS (ES+): m/z = 404 [M + H]+. HRMS:
calcd. for C25H26NO4: 404.1862; found 404.1866.
N-{5-[(1Z)-3-(Diethylamino)-1,2-dimethyl-3-oxoprop-1-enyl]-6-meth-
yl-2-oxo-2H-pyran-3-yl}acetamide (4a): Yield 21%; m.p. 169–
170 °C (Et O/CH Cl ). IR (KBr): ν = 3328 (br), 2974 (m), 2932
˜
2
2
2
(m), 1681 (s), 1627 (s), 1564 (s), 1518 (s), 1430 (s), 1383 (s), 1327
(m), 1289 (m), 1238 (s), 1167 (m), 1123 (m), 1042 (m), 923 (s), 776
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental data, kinetic details, X-ray structure data
and computational details.
1
(s) cm–1. H NMR (300 MHz): δ = 0.81 (t, J = 7.0 Hz, 3 H, Et),
1.10 (t, J = 7.0 Hz, 3 H, Et), 1.88 (s, 3 H, Me), 1.94 (s, 3 H, Me),
2.18 (s, 3 H, Me), 2.20 (s, 3 H, Me), 2.66–3.73 (m, 4 H, Et), 7.91
(br. s, 1 H, NH), 8.03 (s 1 H, =CH-) ppm. 13C NMR (75.5 MHz):
δ = 12.0, 14.2, 16.2, 17.8, 18.4, 24.4, 37.2, 42.1, 117.8, 122.2, 125.8,
126.9, 133.1, 152.3, 159.6, 169.1, 170.7 ppm. MS (EI): m/z (%) =
320 (100) [M]+, 205 (88), 177 (40), 100 (42), 72 (43). HRMS: calcd.
for C17H24N2O4: 320.1736; found 320.1745. C17H24N2O4 (320.39):
calcd. C 63.73, H 7.55, N 8.74; found C 63.82, H 7.89, N 8.89.
Acknowledgments
The Ministry of Higher Education, Science and Technology of the
Republic of Slovenia as well as the Slovenian Research Agency (P1-
0012, P1-0230-0103, and PS-0175) are gratefully acknowledged for
their financial support. G. Milicˇicˇ, K. Zorko, and K. Slanc, Faculty
of Chemistry and Chemical Technology University of Ljubljana,
General Procedure for the Cycloaddition of 2H-Pyran-2-ones 1c–g
with Ethyl Propiolate (10) and Ethyl But-2-ynoate (11):[11f,11g]
A
Eur. J. Org. Chem. 2010, 5870–5883
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5881

ˇ
B. Stefane, A. Perdih et al.
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Published Online: August 31, 2010
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5883