DFT and experimental exploration of intramolecular [2 + 2 + 2] cycloaddition of oxanorbornadienedicarboxylates and analogues

Article abstract of DOI:10.1021/jo4000288

The facile intramolecular [2 + 2 + 2] homo-Diels-Alder cycloadditions of oxanorbornadienedicarboxylates and analogues have been investigated by theoretical calculations using B3LYP and M06-2X density functional methods and experimental confirmation. The oxanorbornadienedicarboxylates formed from furans and but-2-ynedioates undergo the resulting intramolecular [2 + 2 + 2] cycloaddition in a concerted but asynchronous fashion, requiring energy barriers of about 30 kcal/mol to construct five- and three-membered rings simultaneously. Bridgehead substitutents have little influence on the regioselectivity, whereas 5-substitutents involving steric hindrance or electron-acceptor groups are predicted to attenuate the cycloaddition at the substituted side. Furthermore, the linker length, unsaturated bonds, and bridge-ring size are very sensitive to the cyclization rate. Additionally, aza- and norbornadienedicarboxylates demonstrate less reactivity, while thionorbornadienedicarboxylates show more reactivity with the challenge of their synthesis. The intermolecular version was also evaluated in comparison with the intramolecular version. Finally, our experimental tests verified the calculational prediction of the regioselectivity and reactivity.

Full text of DOI:10.1021/jo4000288

Article
pubs.acs.org/joc
DFT and Experimental Exploration of Intramolecular [2 + 2 + 2]
Cycloaddition of Oxanorbornadienedicarboxylates and Analogues
Xinyao Li and Jiaxi Xu*
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing University of
Chemical Technology, 100029 Beijing, People’s Republic of China
S
* Supporting Information
ABSTRACT: The facile intramolecular [2 + 2 + 2] homo-
Diels−Alder cycloadditions of oxanorbornadienedicarboxylates
and analogues have been investigated by theoretical calcu-
lations using B3LYP and M06-2X density functional methods
and experimental confirmation. The oxanorbornadienedicar-
boxylates formed from furans and but-2-ynedioates undergo the resulting intramolecular [2 + 2 + 2] cycloaddition in a concerted
but asynchronous fashion, requiring energy barriers of about 30 kcal/mol to construct five- and three-membered rings
simultaneously. Bridgehead substitutents have little influence on the regioselectivity, whereas 5-substitutents involving steric
hindrance or electron-acceptor groups are predicted to attenuate the cycloaddition at the substituted side. Furthermore, the
linker length, unsaturated bonds, and bridge-ring size are very sensitive to the cyclization rate. Additionally, aza- and
norbornadienedicarboxylates demonstrate less reactivity, while thionorbornadienedicarboxylates show more reactivity with the
challenge of their synthesis. The intermolecular version was also evaluated in comparison with the intramolecular version. Finally,
our experimental tests verified the calculational prediction of the regioselectivity and reactivity.
Scheme 1. Reported Intramolecular [2 + 2 + 2]
Cycloadditions of Oxanorbornadienedicarboxylates
INTRODUCTION
■
Oxanorbornadienedicarboxylates (ONDs) have attracted con-
siderable attention in the realm of biochemistry because of their
powerful ability of fluorogenic probes for the labeling of
proteins. The unique feature of ONDs is the electrophilicity of
a maleate moiety embedded in a homoconjugated bicycle,
which turns out to be realized with the Diels−Alder (D−A)
cycloaddition of another molecule of furan,1 the nucleophilic
addition of organic azides2 and aliphatic thiols,3 and quenching
a pendant dansyl fluorophore via photoinduced electron
transfer.4 In addition, the reactivity and stability of OND
reagents have also been reported with the degradation pathways
including the saponifications and intra-/intermolecular con-
jugative addition, followed by retro-D−A cleavage.5
In addition to the above D−A cycloaddition, hydrolysis,
Michael addition, and retro-D−A reaction pathways, a facile
and efficient intramolecular [2 + 2 + 2] homo-Diels−Alder
cycloaddition of propargylic OND esters in polar media was
encountered by Finn and co-workers during exploration of their
reactivity and stability (Scheme 1).5 OND ester 3 was
generated in situ from furan (1) and dipropargyl but-2-
ynedioate (2), along with γ-lactone product 4, which can be
converted quantitatively from OND ester 3 (Scheme 1, eq 1).
In the case of unsymmetric OND ester 5 that possesses a
substituent at one of the bridgehead carbon atoms, the
cycloaddition was accomplished in an excellent yield without
any regioselectivity (Scheme 1, eq 2). Nonetheless, OND ester
8 with the additional linker length cannot deliver the expected
δ-lactone product, even with a prolonged reaction time
(Scheme 1, eq 3). Likewise, the cyclization of OND ester 9
involving the allyl moiety cannot take place with a prolonged
reaction time (Scheme 1, eq 4).
The metal-free intramolecular [2 + 2 + 2] cycloadditions of
triynes have been widely studied by Ley et al.,6 Roglans et al.,7
and Danheiser et al.8 and investigated theoretically by our9 and
Received: January 7, 2013
© XXXX American Chemical Society
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Houk’s groups.10 To the best of our knowledge, this facile and
novel intramolecular [2 + 2 + 2] cycloaddition of dienynes is a
new potential methodology to construct complex hemi-
basketanes, first discovered by Finn’s group in 2011, without
an in-depth mechanistic investigation. The origins of the
regioselectivity and reactivity are still unclear and await further
studies. Alternatively, we wonder whether oxanorbornadiene-
dicarboxylates could be expanded to their analogues, such as
aza-, thio-, norbornadienedicarboxylates and bicyclo[2.2.1]-
hepa-2,5-dienedicarboxylates to undergo the intramolecular [2
+ 2 + 2] cycloaddition (Scheme 2). Herein, we focus on the
Scheme 2. Proposed Aza-, Thio-, and
Norbornadienedicarboxylates and Bicyclo[2.2.1]hepa-2,5-
dienedicarboxylates for Intramolecular [2 + 2 + 2]
Cycloaddition
Figure 1. Potential energy profile of the tandem cycloaddition reaction
of 1 with 2 (the blue numbers are forming bond distances).
appear to be symmetrical.17,18 The formation of the D−A
adduct 3 is exergonic by 4.8 kcal/mol. The subsequent step is
intramolecular [2 + 2 + 2] cycloaddition with an activation free
energy of 29.9 kcal/mol in water (30.0 kcal/mol in MeCN).
The three forming C−C bond distances in TS2 are 2.40, 2.46,
and 1.88 Å, respectively, indicating that the cycloaddition
occurs in a concerted but asynchronous fashion as well to
construct the novel structure of hemibasketane. The
thermodynamic stable product 4 lies 59.9 kcal/mol below the
substrates. Reviewing the whole energy profiles, we found that
the energies in water and MeCN are very close. Solvation has
small impact on the D−A cycloaddition, with a remarkable
effect on the [2 + 2 + 2] cycloaddition.
2. Substituent Effect on the Regioselectivity. In the
previous experiments, OND ester 5 shows no regioselectivity
in the intramolecular [2 + 2 + 2] cycloaddition, which enhances
the difficulty in the separation of products, even somewhat
limits the application of this novel strategy. Therefore, we are
interested in unraveling which substituents would affect the
regioselectivity (Figure 2). First, the simple model of 1-methyl-
substituted OND ester 5′ was examined. It is expected that the
transition structure TS3-H resembles TS3-Me and both
required activation free energies are very close. The slight
difference is qualitatively consistent with the experimentally
observed poor regioselectivity.
Furthermore, the model of 5-methyl-substituted OND ester
was subjected to further investigation into the regioselectivity.
It is interesting to discover that the 5-methyl-substituted OND
ester was predicted to demonstrate good regioselectivity at the
unsubstituted side since the TS4-H is favored by 4.3 kcal/mol
in free energy relative to TS4-Me. The origin of this vantage
can be understood on the basis of the difference in steric
interactions between the 5- and 6-positions. We had envisioned
that the substituents on the terminal alkyne would increase the
steric interaction to increase the energy barrier. Nonetheless,
similar trends in the regioselectivity were observed in analogous
OND esters substituted by methyl on the terminal propargylic
carbon atom, in which the TS5-H is only 3.7 kcal/mol lower in
free energy than TS5-Me. This erosion of the regioselectivity is
likely attributed to the gauche conformation of the two methyl
groups (45° of the dihedral angle). Thus, the substituents on
unraveling mechanism of the cycloaddition, in particular
concerned about the regioselectivity and reactivity. Moreover,
on the basis of the DFT calculations, we hope to design
norbornadienedicarboxylates and analogues to realize the
cycloaddition experimentally. These findings will not only
provide a good understanding on this novel [2 + 2 + 2]
cycloaddition at the molecular level but also guide further
rational design of new active norbornadienedicarboxylates for
the cycloaddition, while inert norbornadienedicarboxylates are
more useful for use as stable fluorogenic probes.
COMPUTATIONAL METHODS
■
All optimized geometries were calculated at the DFT B3LYP level11
with the 6-311+G(d,p) basis set for all atoms with the Gaussian 09
suite of programs.12 Frequency calculations at the B3LYP level at 298
K were performed to confirm each stationary point to be either a
minimum or a transition structure. Single-point energies based on the
structures obtained at the B3LYP level using the same basis set were
obtained by the M06-2X calculations in order to take the dispersion
energies into consideration.13 Solvation energies were evaluated at the
M06-2X level by a self-consistent reaction field (SCRF) using the
CPCM model, where UFF radii were used. The combined method has
been used recently in calculations of cycloadditions by Houk10,14 and
justified in Table S1 (Supporting Information). The reported energies
are Gibbs free energies in water or acetonitrile solution (ΔGH2O or
ΔGMeCN), Gibbs free energies (ΔG), and zero-point energy-corrected
enthalpies (ΔH). Frontier molecular orbital (FMO) analyses for the
cycloaddition were also employed at the HF/6-31G(d) level with the
former optimized structures.15 Figures 2 and 4 were prepared using
CYLView.16
RESULTS AND DISCUSSION
■
DFT Investigation. 1. Mechanism of the Tandem D−A
and Intramolecular [2 + 2 + 2] Cycloadditions. We provide
the whole potential energy profile of the tandem cycloaddition
process in Figure 1 and various conformers of species with
small differences in energy in Figures S1−S4 (Supporting
Information). The general mechanism shows that the first step
of the cascade reaction corresponding to the D−A cyclo-
addition proceeds via the transition state TS1 with an activation
free energy of 27.1 kcal/mol in a concerted but significantly
asynchronous fashion, and both the diene and dienophile
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Figure 2. Regioselectivity in the intramolecular [2 + 2 + 2] cycloaddition with substituents at different sites.
the terminal alkyne cannot improve the regioselectivity any
more.
From the above analysis, we can propose that the 5-
substituents with steric hindrance or electron-acceptor groups
can increase the energy barrier for the cycloaddition, resulting
in the good regioselectivity at the other side, while the
substituents at the 1-position and terminal alkyne have no
influence on the regioselectivity.
Alternatively, the hydrogen bond between H and F atoms
identified as a key interaction may be responsible for the
reversal in the regioselectivity. To our surprise, the
regioselectivity still remains on unsubstituted side, even more
significantly because TS6-H was found to be 6.1 kcal/mol
lower in free energy than TS6-F. It has been shown that the
distance between the terminal H and F atoms in TS6-F is as
long as 2.53 Å with weak interactions. The NBO charges on the
dienyne moiety of TS6-H and TS6-F were then calculated for
further analysis (Figure 3). It was found that TS6-F has more
notable charge repulsion between forming bonds than TS6-H,
which accounts well for the higher energy level of TS6-F.
Therefore, the electronic effect at the 5-position has a
significant effect on the regioselectivity of the cycloaddition
when the steric hindrance is neglectable.
3. Linker Length and Unsaturated Bonds for the
Reactivity. The linker length and the unsaturated bonds play
an important role on the cyclization rate in Finn’s reaction,
which inspires us to explore the reactivity of the analogous
OND esters 3, 8′, and 9′. The energy profiles drawn in Figure 4
for the comparison imply that OND esters 3 is most facile to
undergo the intramolecular [2 + 2 + 2] cycloaddition, while the
cycloaddition of homopropargyl OND ester 8′ via TS7 suffer
from an activation free energy of 42.5 kcal/mol that appears too
high to allow cyclization to furnish the expected δ-lactone
product 10 under the conditions used. The origin of the low
reactivity of OND ester 8′ can be interpreted in term of the
ring strain force in the precursor of the six-membered lactone
ring in TS7, as the angles around the ring are far from the
normal ones. For OND ester 9′ involving the allylic moiety,
TS8 is found to be 2.3 kcal/mol higher in free energy than TS2,
and the TS8 structure resembles TS2. This slight high energetic
barrier due to the lower reactivity of alkene relative to alkyne,
may have the potential to allow cyclization to proceed under
more harsh conditions.
Figure 3. NBO charges on the dienyne moiety of TS6-H and TS6-F.
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Figure 4. Reactivity of ONDs 3, 8′, and 9′ in the intramolecular [2 + 2 + 2] cycloaddition.
a
Table 1. Energies of the Intramolecular [2 + 2 + 2] Cycloaddition of Aza-, Thio-, and Norbornadienedicarboxylates
a
All energies shown in kcal/mol. The energies in relation to 13 are shown in the parentheses.
4. Hetero- and Norbornadienedicarboxylates for the
Reactivity. The formation and intramolecular [2 + 2 + 2]
cycloaddition reactions of aza-, thio-, and norbornadienedicar-
boxylates were explored extensively (Table 1). When cyclo-
pentadiene 12-C is reacted with 2, norbornadienedicarboxylate
13-C is formed facilely with the lowest activation free energy of
23.3 kcal/mol. The transformation is significantly exergonic by
25.5 kcal/mol to make 13-C thermodynamically stable. The
intramolecular [2 + 2 + 2] cycloaddition reaction of 13-C
requires an activation free energy of 32.5 kcal/mol, which is 2.6
kcal/mol higher than that of 13-O. The energetic barrier of
TS9-N in conversion of pyrrole to azanorbornadienedicarbox-
ylate 13-N is 28.0 kcal/mol, slightly higher than that of TS9-O.
In contrary to other cases, this process is endergonic and
reversible. The following intramolecular [2 + 2 + 2]
cycloaddition requires an activation free energy of 30.1 kcal/
mol, 0.2 kcal/mol higher than that of 13-O. When thiophene
12-S is employed, the transformation suffers from an energetic
barrier that appears too high to allow cycloaddition to proceed
under general thermal conditions. The resulting process has a
tendency to behave similar to the process for oxanorbornadie-
nedicarboxylate. Compared with the four cases, it was found
that X atoms play a crucial role in the formation of hetero- and
norbornadienedicarboxylates, while serving as a micro-regulator
to the intramolecular [2 + 2 + 2] cycloaddition reaction.
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5. Bridge-Ring Size Effect on the Reactivity. Cyclo-
hexadiene 15 is also applicable to the cycloaddition, giving
the bicyclo[2.2.2]octa-2,5-diene-2,3-dicarboxylate 16, a homo-
norbornadienedicarboxylate. The calculational results shown in
Figure 5 demonstrate that the generation of 16 is facile and
Table 2. Energies of the Intramolecular [2 + 2 + 2]
Cycloaddition of Bicyclo[2.2.n]alka-2,5-diene-2,3-
a
dicarboxylates and Key Optimized Geometries
Figure 5. Potential energy profiles of the tandem cycloaddition
reaction of 15 with 2 (the blue numbers are forming/breaking bond
distances).
a
All energies shown in kcal/mol.
thermodynamically stable, whereas the following intramolecular
[2 + 2 + 2] cycloaddition requires a high activation free energy
of 39.0 kcal/mol, making it kinetically unfeasible. In addition,
an alternative conversion of 16 is found to undergo [4 + 2]
cycloreversion with the release of one molecule of ethene to
deliver benzenedicarboxylate 18. The cycloreversion with a free
energy barrier of 29.3 kcal/mol is very competitive to the [2 + 2
+ 2] cycloaddition and predicted to occur under common
thermal conditions. Furthermore, this process is exergonic by
15.8 kcal/mol but exothermic by 0.6 kcal/mol, indicating that
the increase of entropy with the release of ethene is the driving
force of the cycloreversion.
Given the importance of the bridge-ring size, we commenced
investigation of the cycloaddition of series of bicyclo[2.2.n]alka-
2,5-diene-2,3-dicarboxylates (Table 2). When bicyclo[2.2.0]-
hexa-2,5-diene-2,3-dicarboxylate 19-0 was examined, the [2 + 2
+ 2] cycloaddition via TS14-0 required an activation-free
energy as high as 40.0 kcal/mol. It is kinetically unfeasible,
although the substrate 19-0 possesses ring strain and the
conversion is substantially exergonic. The cycloaddition of
bicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate 19-1 requires
an activation free energy of 34.1 kcal/mol, which is the lowest
one in cycloadditions of bicyclo[2.2.n]alka-2,5-diene-2,3-
dicarboxylates. It is also the most predominantly exergonic.
Increasing the bicycle ring to bicyclo[2.2.2]octa-2,5-diene-2,3-
dicarboxylate 19-2 results in an enhanced activation free energy
of 40.5 kcal/mol and a ascending reaction free energy. When an
even larger bicycle [2.2.∞] compound was evaluated, cyclo-
hexa-1,4-diene-1,2-dicarboxylate 19-∞ as a simple model
underwent the cycloaddition with the highest activation free
energy of 53.5 kcal/mol. The adduct 20-∞ was also the least
thermodynamically stable compared with other cases. Review-
ing the whole energy table, we found that only the bicycle
[2.2.1]hepta-2,5-diene-2,3-dicarboxylate was predicted to
undergo the intramolecular [2 + 2 + 2] cycloaddition. Both
increasing and decreasing the bridge-ring size of bicycle [2.2.n]
compounds would enhance energetic barriers and make the
cycloaddition kinetically unfeasible.
From the viewpoint of the structures, it was found that the
ring strain in the formation of cyclopropane has a salient impact
on energetic barriers of the [2 + 2 + 2] cycloaddition. Thus, we
concentrated on the optimized geometries of the formation of
cyclopropane for further discussion. Compounds 19-1 and 19-2
have smaller C2−C6 distances, which are favorable to bond
formation in relation to other two cases. In addition, with
respect to the angle of C2−C1−C6, 19-1 has the smallest
distance, demonstrating the highest activation to the three-
membered ring-closure. More importantly, the dihedral angle of
C2−C4−C1−C6 is essentially related to the nature of the
frontier molecular orbitals (FMOs) (Figure 6). Given the
smallest dihedral angle of 114°, 19−1 exhibits the largest
curved overlap of FMOs, in complete accord with the lowest
activation free energy. Compounds 19-0 and 19-2 possess a
little larger dihedral angle of 117°, both in good agreement with
the higher activation free energies. Increasing the dihedral angle
to 179° in 19-∞ results in the enhanced energetic barrier.
Therefore, the dihedral angle of C2−C4−C1−C6 is the key
geometry for the feasibility of the cycloaddition and decreasing
it would facilitate the transformation.
6. Intermolecular [2 + 2 + 2] Cycloaddition. Finally, the
intermolecular [2 + 2 + 2] cycloaddition reaction was
investigated to compare with the intramolecular one (Table
3). When ethyne (21a) reacted with OND 22, the
intermolecular [2 + 2 + 2] cycloaddition required an activation
enthalpy of 28.8 kcal/mol, which is even 0.4 kcal/mol lower
than that of the intramolecular one. However, the decrease of
the entropy has a significant effect in the intermolecular
cycloaddition, leading to a higher activation free energy of 40.6
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we embarked on the experimental studies of these reactions.
When 2,3,5-trimethylfuran (24) was employed in the reaction
with 2 at 50 °C for 1 h, 1,4,5-trimethyl OND 25 was
successfully obtained in 74% yield. Treatment of 25 in aqueous
acetonitrile at 70 °C for 2 d gave the intramolecular [2 + 2 + 2]
adduct 26 in 65% yield as the sole product, as determined by
1H NMR analysis (eq 5). When the reaction was run at higher
Figure 6. Frontier molecular orbitals and their energies of OND 22
with different alkynes 21 at HF/6-31G(d).
Table 3. Energies of the Intermolecular [2 + 2 + 2]
Cycloaddition of Different Alkynes 21a−b with ONDs 22
a
a
All energies shown in kcal/mol.
kcal/mol. It appears to be remarkably high (7.6 kcal/mol higher
than that of the intramolecular one) and becomes kinetically
unfeasible. When cyclooctyne (21b) is used as an active alkyne,
the activation enthalpy of TS15b drops to 14.2 kcal/mol.
Finally, the activation free energy is only 28.4 kcal/mol, which
is kinetically feasible, although the decrease of the entropy
contributes an energetic portion of 14.2 kcal/mol. Therefore,
the calculational results suggest that only the active alkynes
could be prone to undergo the intermolecular [2 + 2 + 2]
cycloaddition with the low activation enthalpy and the
inescapable decrease of entropy.
From the FMOs in Figure 6, we can see that the HOMO,
HOMO-1, LUMO+2, and LUMO+3 of OND 22 are mostly
localized on the two C−C double bonds, respectively. The
computed results show that the energy gaps between HOMOs
of 22 and LUMO of 21a (11.5 and 13.0 eV) are close to those
between LUMOs of 22 and HOMO of 21a (13.1 and 13.2 eV).
However, both of them appear too high to allow interaction to
proceed. Compound 21b as an active alkyne has enhanced the
FMO energy level relative to 21a, leading to the low energy
gaps between LUMOs of 22 and HOMO of 21b (11.3 eV).
The degressive energy gaps allow the interaction of FMOs to
occur and make the cycloaddition feasible.
or lower temperature, even with prolonged time, the yield
decreased but the regioselectivity was completely consistent
with our calculation results in Figure 4. To confirm the lower
reactivity of the allyl group, we reconducted the reaction of
diallyl OND 9′ under different thermal conditions; however, no
[2 + 2 + 2] cycloaddition was observed (eq 6). In addition,
norbornadienedicarboxylate 13-C was also synthesized by the
cycloaddition of cyclopentadiene and 2 at room temperature in
99% yield.19 It successfully afforded the [2 + 2 + 2] adduct 14-
C in 56% yield under the standard conditions, with recovery of
33% of substrate (eq 7). Prolonging the reaction time did not
improve the yield because of the increasing amount of
decomposition. When pyrrole was reacted with 2, the Michael
adduct 28 was formed instead of azabornadienedicarboxylate
13-N (eq 8).20 It was found that Boc-protecting pyrrole could
take part in the D−A reaction with 2 to give the
azabornadienedicarboxylate 30 in 61% yield,21 along with the
final intramolecular [2 + 2 + 2] adduct 31 in 8% yield. We
realized the intramolecular [2 + 2 + 2] cycloaddition of
azobornadienedicarboxylate 30 although it showed low
conversion into adduct 31 only in 10% yield under the
Experimental Verification for the DFT Prediction. To
verify our prediction that the 5-substituted OND can undergo
intramolecular [2 + 2 + 2] cycloaddition to afford the sole
product regioselectively and to gain more information about
the reactivity of aza-, thio-, and norbornadienedicarboxylates,
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were prepared by acid-catalyzed esterification of acetylenedicarboxylic
acid with azeotropic removal of water as described by Finn.5 2,3,5-
Trimethylfuran (24) was prepared from 3-methylhexane-2,5-dione by
the general procedure of the Paal−Knorr synthesis method.25
General Procedure for Synthesis of ONDs 25 and 9′. A
solution of a furan (2 mmol) and acetylenedicarboxylate 2 (380 mg, 2
mmol) was stirred at 50 °C for 1 h. The residue was chromatographed
on a column of silica gel with ethyl acetate and petroleum ether (1:10,
v/v) as an eluent.
standard conditions (eq 9). On the other hand, the inert aza-
and norbornadienedicarboxylates can be considered as stable
fluorogenic probes. The synthesis of thionorbornadienedicar-
boxylates still remained a challenge after our endeavor.
1,3-Cyclohexadiene was also applicable to the D−A reaction,
giving the bicyclodienedicarboxylate 16 in 95% yield, along
with 5% yield of phthalate 18, which arose from a [4 + 2]
cycloreversion with the release of one molecule of ethene.22
Treatment of bicyclodienedicarboxylate 16 under the standard
cycloaddition conditions did not result in the [2 + 2 + 2]
adduct 17 and phthalate 18, whereas a solution of 16 in toluene
was refluxed for 30 h to afford phthalate 18 in 91% (eq 10).
These experimental findings gave concrete evidence to support
the computational predictions.
For the intermolecular [2 + 2 + 2] cycloaddition, there has
been one and only one report that aza-, oxa-, and
norbornadienedicarboxylates react with cyclooctyne in
CH2Cl2 at 100 °C for 4 d to give intermolecular [2 + 2 + 2]
adducts in 11−31% yields (eq 11).23 Our calculations in Table
3 are once again consistent with the experimental results.
Diprop-2-ynyl 1,4,5-trimethyl-7-oxabicyclo[2.2.1]hepta-2,5-
diene-2,3-dicarboxylate (25): isolated yield 74% (444 mg); pale
1
yellow oil; Rf 0.38 (20% EtOAc/petroleum ether); H NMR (400
MHz, CDCl3) δ 6.42 (d, J = 1.6 Hz, 1H), 4.79 (d, J = 2.0 Hz, 4H),
2.50 (t, J = 2.0 Hz, 2H), 1.90 (d, J = 1.6 Hz, 3H), 1.77 (s, 3H), 1.73 (s,
3H); 13C NMR (100.6 MHz, CDCl3) δ 163.4, 163.3, 157.7, 155.6,
154.9, 138.6, 93.6, 91.4, 77.4, 75.6, 52.7, 52.7, 15.7, 13.9, 13.0. IR
(KBr) νmax 3278, 2937, 2129, 1773, 1719, 1356, 1271, 1232, 1205,
+
1114, 988 cm−1; HRMS (ESI) calcd for C17H20NO5 [M + NH4 ]
318.1341, found 318.1338.
Diallyl 7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (9′):
isolated yield 44% (230 mg); pale yellow oil; Rf 0.30 (20% EtOAc/
1
petroleum ether); H NMR (400 MHz, CDCl3) δ 7.23 (s, 2H), 5.93
(ddt, J = 17.2, 10.4, 6.0 Hz, 2H), 5.70 (s, 2H), 5.36 (dd, J = 17.2, 1.2
Hz, 2H), 5.27 (dd, J = 10.4, 1.2 Hz, 2H), 4.71 (ddd, J = 6.0, 1.2, 1.2
Hz, 4H); 13C NMR (100.6 MHz, CDCl3) δ 162.7, 153.0, 143.4, 131.5,
119.1, 85.3, 66.1; IR (KBr) νmax 3084, 3025, 2952, 1711, 1640, 1270,
1206, 1111, 989, 932, 709 cm−1; HRMS (ESI) calcd for C14H15O5 [M
+ H+] 263.0919, found 263.0910; calcd for C14H14NaO5 [M + Na+]
285.0739, found 285.0731.
CONCLUSIONS
■
In summary, we have explored the facile intramolecular [2 + 2
+ 2] homo-D−A cycloaddition of oxanorbornadienedicarbox-
ylates and their analogues with the aid of the DFT calculations
and experimental confirmation. The oxanorbornadienedicar-
boxylates were generated from furans and but-2-ynedioates and
undergo the resulting intramolecular [2 + 2 + 2] cycloaddition
in a concerted but asynchronous fashion with slightly higher
energy barriers to construct the complex hemibasketanes.
Bridgehead substituents have little influence on the regiose-
lectivity, whereas 5-substituents involving steric hindrance or
electron-acceptor groups are predicted to attenuate the
cycloaddition at the substituted side. Furthermore, the alkene
moiety is much less reactive relative to alkyne, and a linker
length longer than five atoms shows significantly disfavored
energy barrier due to the ring stain in the transition state.
Additionally, aza- and norbornadienedicarboxylates demon-
strate less reactivity, while thionorbornadienedicarboxylates
show more reactivity, but with the challenge of their synthesis.
The bridge-ring size plays a crucial role that only the
bicyclo[2.2.1]hepa-2,5-dienedicarboxylates can undergo the
cycloaddition feasibly. The corresponding intermolecular
reaction was also evaluated to compare with the intramolecular
one, in which the active alkynes are indispensable. Eventually,
our experimental results comfirm the calculational prediction of
the regioselectivity at the 5-unsubstituted side, slightly less
reactivity of aza- and norbornadienedicarboxylates, and
competitive cycloreversion reaction of bicyclo[2.2.2] octa-2,5-
dienedicarboxylates.
Diprop-2-ynyl Bicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate
(13-C). According to a literature procedure,19 acetylenedicarboxylate
2 (380 mg, 2 mmol) was added dropwise to freshly distilled
cyclopentadiene (132 mg, 2 mmol), cooling the mixture with a water
bath when the temperature exceeded 45 °C. The mixture was stirred
for an additional 1 h. The resulting (505 mg, 99% yield) of colorless oil
is pure diprop-2-ynyl bicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate
(13-C) by 1H NMR: Rf 0.27 (20% EtOAc/petroleum ether); 1H NMR
(400 MHz, CDCl3) δ 6.93 (s, 2H), 4.83 (d, J = 2.4 Hz, 2H), 4.79 (d, J
= 2.4 Hz, 4H), 3.98 (s, 2H), 2.57 (t, J = 2.4 Hz, 1H), 2.50 (t, J = 2.4
Hz, 2H), 2.31 (d, J = 6.8 Hz, 1H), 2.12 (d, J = 6.8 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3) δ 164.1, 152.7, 142.5, 77.4, 75.4, 73.3, 53.7, 52.6;
IR (KBr) νmax 3291, 2946, 2129, 1719, 1624, 1375, 1250, 714 cm−1;
HRMS (ESI) calcd for C15H13O4 [M + H+] 257.0814, found 257.0811.
Diprop-2-ynyl 2-(pyrrol-2-yl)butenedioate (28). As the literature
procedure,20 a solution of pyrrole (134 mg, 2 mmol) and
acetylenedicarboxylate 2 (380 mg, 2 mmol) was stirred at room
temperature for 1 h. The brown solution was chromatographed on a
column of silica gel with ethyl acetate and petroleum ether (1:10, v/v)
as an eluent to afford diprop-2-ynyl 2-(pyrrol-2-yl)butenedioate (28)
as yellow crystals: 231 mg, yield 45%; mp 86−87 °C; Rf 0.50 (20%
1
EtOAc/petroleum ether); H NMR (400 MHz, CDCl3) δ 12.42 (s,
1H), 7.08 (d, J = 0.6 Hz, 1H), 6.82 (m, 1H), 6.32 (dt, J = 4.0, 2.4 Hz,
1H), 5.99 (s, 1H), 4.89 (d, J = 2.4 Hz, 2H), 4.80 (d, J = 2.4 Hz, 2H),
2.56 (t, J = 2.4 Hz, 1H), 2.52 (t, J = 2.4 Hz, 1H); 13C NMR (100.6
MHz, CDCl3) δ 167.8, 166.8, 139.1, 125.8, 124.7, 119.1, 111.1, 108.9,
77.4, 76.9, 75.9, 75.4, 53.4, 52.8; IR (KBr) νmax 3291, 2923, 2129,
1735, 1686, 1578, 1401, 1368, 1284, 1216, 1182, 753 cm−1; HRMS
(ESI) calcd for C14H12NO4 [M + H+] 258.0766, found 258.0759.
7-tert-Butyl 2,3-Di(prop-2-ynyl) 7-Azabicyclo[2.2.1]hepta-2,5-
diene-2,3,7-tricarboxylate (30). Based on the literature procedure,21
a solution of N-Boc-pyrrole 29 (167 mg, 1 mmol) and
acetylenedicarboxylates 2 (951 mg, 5 mmol) in 10 mL of toluene
was stirred at 70 °C for 24 h. The volatiles were removed under
vacuum, and the residue was then purified by silica gel flash
chromatography with ethyl acetate and petroleum ether (1:10, v/v,
then 1:5, v/v) as an eluent to afford 7-tert-butyl 2,3-di(prop-2-ynyl) 7-
azabicyclo[2.2.1]hepta-2,5-diene-2,3,7-tricarboxylate (30) as a color-
less oil: 218 mg, yield 61%; Rf 0.35 (20% EtOAc/petroleum ether); 1H
NMR (400 MHz, CDCl3) δ 7.15 (s, 2H), 5.50 (s, 2H), 4.81 (d, J = 2.0
Hz, 4H), 2.51 (t, J = 2.4 Hz, 1H), 1.41 (s, 9H); 13C NMR (100.6
EXPERIMENTAL SECTION
■
General Information. Melting points were obtained on a melting
point apparatus and are uncorrected. All NMR spectra were recorded
on a 400 MHz spectrometer with TMS as an internal standard in
CDCl3 solution, and the chemical shifts (δ) are reported in ppm. IR
spectra were determined directly. MS spectra were obtained on an ESI
mass spectrometer. HRMS spectra were performed by the ESI
ionization technique on an LC/MSD TOF mass spectrometer. TLC
separations were performed on silica gel GF254 plates, and the plates
were visualized with UV light.
Furan, cyclopentadiene, pyrrole, and 1,3-cyclohexadiene were
commercially available, whereas N-Boc-pyrrole (29) was synthesized
according to the previous reports.24 Acetylenedicarboxylates 2 and 27
G
dx.doi.org/10.1021/jo4000288 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
MHz, CDCl3) δ 154.0, 81.8, 77.0, 75.7, 69.1, 53.0, 28.2; IR (KBr) νmax
3286, 2979, 2130, 1778, 1716, 1631, 1257, 1162, 677 cm−1; HRMS
(ESI) calcd for C19H19NNaO6 [M + Na+] 380.1110, found 380.1109.
Diprop-2-ynyl Bicyclo[2.2.2]octa-2,5-diene-2,3-dicarboxylate
(16). Based on a literature procedure,22 a solution of 1,3-cyclo-
hexadiene (240 mg, 3 mmol) and acetylenedicarboxylates 2 (380 mg,
2 mmol) in 20 mL of toluene was stirred at 70 °C for 12 h. The
volatiles were removed under vacuum, and the residue was then
purified by silica gel flash chromatography with ethyl acetate and
petroleum ether (1:10, v/v) as an eluent to afford diprop-2-ynyl
bicyclo[2.2.2]octa-2,5-diene-2,3-dicarboxylate (16) as a colorless oil:
(100.6 MHz, CDCl3) δ 166.4, 131.4, 131.1, 129.1, 76.7, 75.4, 53.1; IR
(KBr) νmax 3279, 2923, 2854, 2128, 1724, 1598, 1268, 743 cm−1;
HRMS (ESI) calcd for C14H11O4 [M + H+] 243.0657, found
243.0652; calcd for C14H10NaO4 [M + Na+] 265.0477, found
265.0471.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR and HRMS spectra for all new compounds,
justification of computational methods, calculation of con-
formations in the [2 + 2 + 2] cycloaddition, computational
details of energies, and coordinates of all stationary points. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
513 mg, yield 95%; Rf 0.56 (20% EtOAc/petroleum ether); H NMR
(400 MHz, CDCl3) δ 6.39 (t, J = 3.6 Hz 2H), 4.78 (d, J = 2.0 Hz, 4H),
4.08 (s, 2H), 2.50 (s, 2H), 1.50 (d, J = 7.8 Hz, 2H), 1.42 (d, J = 7.7
Hz, 2H); 13C NMR (100.6 MHz, CDCl3) δ 165.1, 142.3, 133.7, 75.4,
52.7, 39.1, 24.6; IR (KBr) νmax 3288, 2946, 2875, 2130, 1717, 1642,
1377, 1257, 706 cm−1; HRMS (ESI) calcd for C16H15O4 [M + H+]
271.0970, found 271.0966; calcd for C16H14NaO4 [M + Na+]
293.0790, found 293.0783.
General Procedure for the Intramolecular [2 + 2 + 2]
Cycloaddition.5 Oxa-, aza-, or norbornadienedicarboxylate precursor
(0.5 mmol) was dissolved in MeCN (10 mL). Water (10 mL) was
added, and the reaction mixture was heated at 70 °C for 2 d. The
reaction mixture was concentrated and the residue was purified by
silica gel flash chromatography with ethyl acetate and petroleum ether
(1:10, v/v, then 1:4, v/v) as eluent.
AUTHOR INFORMATION
Corresponding Author
*Tel: +86-10-6443-5565. Fax: +86-10-6443-5565. E-mail:
jxxu@mail.buct.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project was supported by the National Natural Science
Foundation of China (Nos. 21172017, 20972013 and
20772005), the specialized Research Fund for the Doctoral
Program of Higher Education, Ministry of Education of China
(No. 20110010110011), and “CHEMCLOUD COMPUT-
ING” of Beijing University of Chemical Technology.
Prop-2-ynyl 8,10,11-trimethyl-3,9-dioxa-2-oxopentacyclo-
[6.4.0.01,5.07,11.010,12]dodec-5-ene-12-carboxylate (26): isolated yield
65% (97 mg); colorless crystals; mp 177−178 °C; Rf 0.23 (25%
1
EtOAc/petroleum ether); H NMR (400 MHz, CDCl3) δ 6.06 (s,
1H), 5.11 (dd, J = 14.0, 2.0 Hz, 1H), 5.01 (d, J = 14.0 Hz, 1H), 4.81
(dd, J = 15.6, 2.0 Hz, 1H), 4.58 (dd, J = 15.6, 2.0 Hz, 1H), 2.85 (d, J =
3.2 Hz, 1H), 2.47 (t, J = 2.0 Hz, 3H), 1.87 (s, 3H), 1.32 (s, 3H), 1.23
(s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 172.8, 167.1, 145.8, 122.2,
104.7, 79.3, 77.0, 75.5, 68.0, 65.4, 65.0, 52.5, 51.6, 51.3, 10.4, 9.6, 7.6;
IR (KBr) νmax 3262, 2938, 2132, 1758, 1707, 1445, 1389, 1358, 1321,
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The Journal of Organic Chemistry
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