Competitive Pseudopericyclic [3,3]- and [3,5]-Sigmatropic Rearrangements of Trichloroacetimidates

Article abstract of DOI:10.1021/acs.joc.5b01355

The Woodward-Hoffmann rules predict whether concerted pericyclic reactions are allowed or forbidden based on the number of electrons involved and whether the cyclic orbital overlap involves suprafacial or antarafacial orbital overlap. Pseudopericyclic reactions constitute a third class of reactions in which orthogonal orbitals make them orbital symmetry allowed, regardless of the number of electrons involved in the reaction. Based on the recent report of eight-centered ester rearrangements, it is predicted that the isoelectronic eight-centered rearrangements of imidates would also be allowed. We now report that these rearrangements occur, and indeed, an eight-centered rearrangement is slightly favored in at least one case over the well-known six-centered Overman rearrangements, in a trichloroacetimidoylcyclohexadienone, a molecular system where both rearrangements are possible.

Full text of DOI:10.1021/acs.joc.5b01355

Article
pubs.acs.org/joc
Competitive Pseudopericyclic [3,3]- and [3,5]-Sigmatropic
Rearrangements of Trichloroacetimidates
Shikha Sharma, Trideep Rajale, Daniel K. Unruh, and David M. Birney*
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States
S
* Supporting Information
ABSTRACT: The Woodward−Hoffmann rules predict whether concerted pericyclic reactions are allowed or forbidden based
on the number of electrons involved and whether the cyclic orbital overlap involves suprafacial or antarafacial orbital overlap.
Pseudopericyclic reactions constitute a third class of reactions in which orthogonal orbitals make them orbital symmetry allowed,
regardless of the number of electrons involved in the reaction. Based on the recent report of eight-centered ester rearrangements,
it is predicted that the isoelectronic eight-centered rearrangements of imidates would also be allowed. We now report that these
rearrangements occur, and indeed, an eight-centered rearrangement is slightly favored in at least one case over the well-known
six-centered Overman rearrangements, in a trichloroacetimidoylcyclohexadienone, a molecular system where both
rearrangements are possible.
provided.5−26 Four general characteristics have been suggested
INTRODUCTION
■
for pseudopericyclic reactions:2,5,8 (1) planar, or close to planar
transition states5−7,13−16 (2) low, or even nonexistent barriers,
particularly when the transition state geometry is favor-
able,2,5−7,13−26 (3) nonaromatic transition states,15,18,20,26 and
(4) perhaps most significantly and the focus of this work, no
pseudopericyclic reaction can be forbidden.5−7,9,11 In particular,
we have predicted6,7 and subsequently experimentally demon-
strated8,10 examples of concerted thermal reactions of esters
that proceed via eight-centered cyclic transition states. These
reactions would be forbidden by the Woodward−Hoffmann
rules1 but are orbital-symmetry-allowed with a pseudopericyclic
orbital topology.2
It would be difficult to overstate the importance of the
Woodward−Hoffmann rules in modern organic chemistry.1
This triumph of molecular orbital theory led to clear and
consistent explanations of pericyclic reactions and codified the
application of the conservation of orbital symmetry to a wide
range of reactions. Quite simply, the rules predict whether the
reaction is allowed or forbidden based on the number of
electrons involved and whether the cyclic orbital overlap is
suprafacial or antarafacial.
However, not long after the publication of the rules, Lemal
recognized a third possibility.2 If bonding and nonbonding
orbitals on the same atom exchange roles during a pericyclic
reaction, then these orthogonal orbitals can result in a
transition-state geometry that lacks cyclic orbital overlap
around the ring of atoms that undergo bonding changes.
Lemal described such reactions as pseudopericyclic and
recognized that all such reactions with this orbital topology
would be allowed by orbital symmetry, regardless of the
number of electrons involved.3,4
Acetoxycyclohexadienones (e.g., 1) have long been known to
undergo formal [3,5]-sigmatropic thermal rearrangements,
beginning with the pioneering work of Wessely.29 Two
mechanisms were suggested for the formation of 4 and 5,
either two sequential Woodward−Hoffmann-allowed [3,3]-
rearrangements via 3 and 2 or a direct [3,5]-rearrangement via
2 (Scheme 1) followed by tautomerization. The latter would be
unable to achieve a [3s,5a] transition-state geometry, and a
Since that time, there have been extensive efforts from our
laboratory,5−10 along with numerous insightful studies from
other groups, both experimental11,12 and computational,13−26
exploring the scope of pseudopericyclic reactions. Aspects of
this work have recently been reviewed,27,28 and so only leading
references to the extensive literature on these reactions are
Special Issue: 50 Years and Counting: The Woodward-Hoffmann
Rules in the 21st Century
Received: June 15, 2015
© XXXX American Chemical Society
A
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transition state, in contrast to the cyclic delocalization in
pericyclic reactions.1 The calculated barrier for the thermal
[1,3]-rearrangement is substantially higher than for the [3,3];
this is consistent with the experimental observation of exclusive
[3,3]-rearrangement.26 This is arguably due to angle strain in
the four-centered transition state. In contrast, pseudopericyclic
[3,5]-rearrangements of esters are favored over the more
familiar [3,3]-rearrangements (Scheme 1);10 there is presum-
ably less strain in an eight-centered transition state. Therefore,
it is anticipated that a pseudopericyclic [3,5]-rearrangement
would also be allowed and might be observable in the case of
imidates as well.
Scheme 1. Rearrangements of 2-Acetoxy-2-methyl-3,5-
cyclohexadienone (1)
We first proposed the study of imidate 8 (Scheme 4), which
possesses a dienyl moiety in a conformation suitable for either
[3,3]- or [3,5]-sigmatropic rearrangements.34 Hence, we
anticipated that it could rearrange into either or both
intermediates 9 and 11 via facile [3,5]- and [3,3]-rearrange-
ments, respectively, followed by tautomerization to the
corresponding phenols 10 and 12. A second [3,3]-rearrange-
ment of the amide 11 to form imidate 13 and then 14 would
not be expected to be favored simply because amides are much
more stable than imidates. In any case, the [3,3]-, direct [3,5]-,
and sequential [3,3]-rearrangement mechanisms would give
readily distinguishable isomeric structures 10, 12, and 14.
Identification of products would answer the question of
whether the [3,5]-rearrangement occurs or not. Computational
studies (B3LYP/6-31G(d,p)) reported below concur with the
qualitative theory and suggest that both of the [3,3]- and [3,5]-
rearrangements would be allowed.
[3s,5s] transition state would be predicted to be forbidden by
the Woodward−Hoffmann rules.1
More recent qualitative theory has suggested that partic-
ipation of ester lone pairs renders all thermal reactions of esters
allowed via pseudopericyclic transition states.6−8,10 Indeed,
experimental studies from this laboratory on the thermal
rearrangement of acetoxycyclohexadienone (1) have recently
shown that 4 and 5 are the major products and 6 is the minor
product, extrapolated to time zero.10 This demonstrates that
the [3,5]-sigmatropic rearrangement occurs in preference to the
[3,3]-rearrangement.10 Computations suggested that the [3,5]-
rearrangement proceeds by a lower barrier pseudopericyclic
transition state in agreement with the experimental prefer-
ence.6,7,10 To extend the scope of these rearrangements, we
have proposed the design and synthesis of isoelectronic26,30
trichloroacetimidate derivatives (Scheme 2) that can undergo
similar pseudopericyclic [3,3]- and [3,5]-sigmatropic rearrange-
ments to give the corresponding trichloroacetamide derivatives.
RESULTS AND DISCUSSION
■
Synthetic Approaches to Trichloroacetimidate 8.
However, synthetic access to 8 proved challenging. Wessely
oxidation29 of o-cresol using Pb(OAc)4/AcOH yields the
acetate 1 as a yellow solid in reasonable yield.10,35−38 Ester
hydrolysis of 1 may occur under some conditions, but the
corresponding alcohol (7) could not be isolated.35−38
Hydrolysis of 1 in basic methanol is known to give the ring-
opened keto ester (Scheme 5).35 Hydrolysis under acidic
conditions led to the formation of 15 via the well-precedented
Diels−Alder dimerization of alcohol 7.36−38
Scheme 2. Acetate (X = O) and Imidate (X = NH) [3,5]-
Rearrangements Are Isoelectronic and Pseudopericyclic,
with Orbital Disconnections at the Breaking and Forming σ-
Bonds
The known propensity of sterically unencumbered cyclo-
hexadienones to undergo Diels−Alder reactions36−38 suggested
8 could be accessed via protection/deprotection approach, as
shown in Schemes 6 and 7. Pyrolysis of 18 could lead to 8 via a
retro-Diels−Alder reaction. Under the pyrolysis conditions, 8
would be expected to then undergo the thermal rearrangements
outlined in Scheme 4 and Scheme 7. For the synthesis of 18
(Scheme 6), acetate 1 was refluxed with freshly cracked
cyclopentadiene39 in xylene to yield the [4 + 2] cycloaddition
product 16. This Diels−Alder adduct was smoothly hydrolyzed
to the corresponding alcohol 17 using 10% NaOH(aq). Alcohol
17 was then treated with KH as base, followed by addition of
trichloroacetonitrile in dry THF. The expected trichloroaceti-
midate 18 was not obtained under these standard con-
ditions.40,41 Instead, the tetracyclic adduct 19 was obtained,
presumably via the intermediacy of the less stable isomer 18.
The structure of 19 was confirmed by 1H and 13C NMR as well
as an X-ray crystal structure (Figure 1). Authentic samples of
compounds 10 and 12 (to serve as GC standards) were
synthesized from the corresponding anilines by treatment with
hexachloroacetone in hexane at 65−70 °C.
The Overman rearrangement of allylic imidates is a
synthetically useful method for the synthesis of allylic amines,
amino acids, and other organic scaffolds with transposition of
the functional groups30−33 (Scheme 3). The calculated
transition states for imidate [1,3]- and [3,3]-sigmatropic
rearrangements have been recognized as pseudopericyclic,26
based on analyses showing localized electron density in the
Scheme 3. Overman Rearrangement of Imidates
B
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Scheme 4. Proposed Rearrangements of Cyclohexadienyl Trichloroacetimidate (8)
Scheme 5. Attempted Hydrolysis of Acetate 1
Scheme 6. Synthesis of 19
Scheme 7. Anticipated Thermolysis Products of 19
Flash Vacuum Pyrolysis of 19. Flash vacuum pyrolysis
(FVP) proved to be extremely useful in studying the
mechanism of [3,3]- and [3,5]-sigmatropic rearrangements in
acetoxycyclohexadienone 1.10 Despite our initial disappoint-
ment that 18 could not be isolated, 19 was nevertheless
subjected to FVP (details in the Supporting Information)
between a temperature range of 400−550 °C. The product
mixture was collected in a cold trap. The results of the FVP are
summarized in Table 1.
FVP of 19 at these high temperatures gave a complex mixture
of products, most of which were not identified. However, the
amide 10 expected from [3,5]-rearrangement of 8 was
1
identified in this mixture by GC, GC−MS, and H NMR
comparison to an authentic sample. There is no evidence as to
whether the retro-Diels−Alder reaction or the ring opening
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subsequent reaction under these harsh conditions. It could also
be that the keto tautomer 11 from the [3,3]-rearrangement was
the species that decomposed, while 9 from the [3,5]-
rearrangement underwent intramolecular tautomerization to
the stable phenol 10 (see calculations and Figure 3, below), in
analogy to the reactions calculated for 1.10
Among the unidentified peaks in the GC−MS was one that
showed a molecular ion and fragmentation pattern similar to 10
and 12, but at a different retention time. Based solely on this
limited GC−MS data, this might have been 20. This would
require the retro-Diels−Alder of 19 to directly form 20 and the
survival of 20 unchanged during the FVP. If 8 were formed in
the FVP, it would be expected to rapidly rearrange to 10 or 12.
Synthesis of 22. The observation of the [3,5]-rearrange-
ment product 10 was encouraging. However, in light of the
complex product mixture obtained from FVP of 19, we sought
a structurally similar molecular system that was simpler and
might be expected to give a cleaner product mixture. The
complication with the imidate 8 was the dimerization of the
dienone alcohol 7. Thus, we sought a dienone alcohol that
would not undergo Diels−Alder dimerization.
There is precedent that monomeric cyclohexadienone
alcohols can be isolated if the system is sufficiently crowded.
The [4 + 2]-Diels−Alder dimerization can be blocked merely
by introducing a small alkyl or alkoxy substituent to the C-5
position of the 2,4-cyclohexadienone system.42,43 Oxidative
dearomatization of 2,3,5-trimethylphenol has been reported
using SIBX as the oxidant, albeit in only 12% isolated yield of
the desired alcohol 21.43
Figure 1. X-ray diffraction crystal structure of 19. Thermal ellipsoids
are represent at 50% probability.
a
Table 1. Flash Vacuum Pyrolysis of 19
temp (°C)
% 19
% [3,5]-product 10
% unidentified products
400
450
500
550
98
79
0
0
2
7
8
2
19
93
92
0
a
Note: The FVP was carried out using 50 mg of 19 and was
performed according to the general procedure described in the
Supporting Information. The percentages of products are based on
uncorrected GC integrations.
The hydroxytrimethylcyclohexadienone 21 has also been
prepared in modest (35%) yield by periodate oxidation.42 In
our hands, 21 was obtained in 40% yield (Scheme 8 and Figure
2a). We anticipated that subsequent formation of the imidate
22 would be straightforward when 21 was subjected to standard
conditions for the formation of trichloroacetimidates.40,41 1H
and 13C NMR of the product in CDCl3 showed 22, along with
the ring-closed isomer 23, in analogy to 19.44 When the
mixture of 22 and 23 was crystallized from pentane as solvent,
X-ray diffraction showed that the crystals consisted solely of 23
(Figure 2b).
occurred first, i.e., whether the reaction occurred as 19 to 18 to
8 or occurred as 19 to 20 to 8, but the formation of 10 seems
to require the intermediacy of 8.
FVP at 400 °C resulted in only 2% conversion of 19,
indicating that the retro-Diels−Alder reaction required higher
temperatures. (The barrier for the [3,3]- and [3,5]-rearrange-
ment of trichloroacetimidates is expected to be lower than the
retro-Diels−Alder.26,30−33) When the temperature was raised to
450 °C, about 79% of 19 was unreacted, but cyclopentadiene
1
was observed in the H NMR, indicating that the retro-Diels−
Alder reaction occurred. Approximately 2% of the [3,5]-
rearranged product 10 was observed as indicated by GC and
GC−MS. The remaining peaks were unidentified. At 500 and
550 °C, there was no starting compound 19 left in the pyrolysis
mixture. A modest amount of the product 10 from [3,5]-
rearrangement was observed (7% at 500 °C and 8% at 550 °C).
The amide 12 anticipated from the [3,3]-rearrangement of 8
was not observed in the complex product mixtures obtained
from FVP at any temperatures (400−550 °C). It may be that
12 was not formed, but it also might be that 12 underwent a
Dissolution of crystalline 23 in CDCl3 gave the original
1
mixture of 22 and 23. H NMR spectra were then obtained in
three other solvents of varying polarity (CCl4, benzene-d6, and
acetone-d6). The proportion of 22 in each solvent is presented
in Table 2. With the increase in dielectric constant of the
solvents CCl4, benzene-d6, and CDCl3 there is an increase in
the percentage of ring-opened isomer 22. However, in the case
of deuterated acetone which has a dielectric constant of 20.7,
only the ring-closed isomer 23 was observed. This can be
Scheme 8. Synthesis of 22, 23, and the Byproduct 24
D
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Figure 2. (a) Crystal structure of 21. (b) Crystal structure of 23. Thermal ellipsoids are represent at 50% probability.
Table 2. Percentage of 22 in Equilibrium with 23 in
Different solvents by H NMR
Table 3. Thermolysis and FVP of 23
1
temp (°C)
% 23
% 25
% 26
ratio 25:26
1H NMR Solvents
% 22
dielectric constant
a
d
60 (18 h)
80
0
14
69
65
60
58
6
31
35
40
42
2.3:1
a
c
CCl4
28
37
69
0
2.24
2.27
4.87
20.7
70 (15 h)
2.2:1
a
d
benzene-d6
CDCl3
80 (12 h)
0
1.9:1
b
c
300
0
1.5:1
b
d
acetone-d6
400
0
1.4:1
a
b
c
Thermolysis in benzene-d6. Flash vacuum pyrolysis. Ratios are
d
1
based on GC integration. Ratios are based on H NMR integration.
rationalized by assuming that acetone can hydrogen bond with
the hydroxyl group present in 23 and thus stabilize the ring-
closed isomer. We calculated the relative energies of the two
isomers at the B3LYP/6-31G(d,p) level to assess the energies
of 22 and 23 using the SCRF polarizable continuum model for
these solvent dielectric constants, and a similar trend in the
stability of ring opened 22 and ring closed 23 was observed,
where a higher dielectric constant stabilized the ring-opened
form 22 (see the Supporting Information).
under the GC conditions (injector temperature of 160 °C).
This suggested that much lower temperatures could still lead to
the rearrangements. Indeed, heating 23 at 80 °C in benzene-d6
for 12 h resulted in complete conversion of 23 into 25 and 26
1
in a 1.9:1 ratio by H NMR integration. Heating a sample in
benzene-d6 at 60 °C for 18 h led to 20% conversion to 25 and
1
26 in a 2.3:1 ratio by H NMR integration. Continued heating
Thermal Rearrangements of 22. To study the [3,3]- and
[3,5]-rearrangements of 22 and/or 23, we conducted gas-phase
FVP studies as well as thermolysis in benzene-d6 solution; the
results are summarized in Scheme 9 and Table 3. FVP was
conducted at 300 and 400 °C. The product mixtures were
of this sample at 70 °C for an additional 15 h led to complete
disappearance of 23 and formation of 25 and 26 in a 2.2:1 ratio
by GC analysis.45
Computational Details. To complement the experimental
studies and to shed light on the mechanism of the
rearrangements, a brief computational study was undertaken.
Most of the calculations were carried out using the Gaussian09
suite of programs.46 The geometries of the reactants,
intermediates, transition states, and products were optimized
with the B3LYP functional47 using the 6-31G(d,p) basis set.48
Transition states and minima were verified by frequency
calculations. Multiple conformations of 8, 9, and 11 were
calculated. The relative energies of the lowest energy
conformations and transition states are presented graphically
in Figure 3, and the energies discussed in the text are the
B3LYP/6-31G(d,p) free energies unless otherwise noted.
Transition states [3,5]-TS2 and [3,3]-TS1 are for the [3,5]-
1
analyzed by H NMR, GC, and GC−MS. Both these FVP
reactions were clean and generated only 25 ([3,5]-rearranged
product) and 26 ([3,3]-rearranged product) with no starting
1
material remaining by H NMR. The product distribution was
analyzed by GC; comparison with authentic samples showed a
1.5:1 ratio of 25 to 26 at 300 °C, favoring the [3,5]-
rearrangement (see the Supporting Information for GC
conditions). Control experiments showed that these amides
(25 and 26) are stable under the GC conditions. But the barrier
for the [3,3]-rearrangements of imidates26,30,31 is lower than for
ester rearrangements,10 so it was not surprising that control
experiments showed that the starting compound 23 rearranged
Scheme 9. Thermal [3,3]- and [3,5]-Rearrangement of 23
E
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Figure 3. Free energy profile, ΔGgas, for the [3,3]- and [3,5]-sigmatropic rearrangements of compound 8 at the B3LYP/6-31G(d,p) level of theory at
723.15 K.
Figure 4. Transition-state geometries calculated at the B3LYP/6-31G(d,p) level of theory for thermal reactions of 8. Distances of breaking and
forming bonds in angstroms.
and [3,3]-rearrangement of 8 to 9 and 11, respectively.
Additionally, 22 and 23 were optimized at the B3LYP/6-
31G(d,p) level and single-point energies were calculated using
the polarizable dielectric continuum model.49 Further computa-
tional details and geometries of all structures are provided in
the Supporting Information. Additional computational studies
are in progress.
Computational Results. In our earlier work, we have
shown that the [3,5]-sigmatropic rearrangement of esters is
allowed via a low energy, concerted pseudopericyclic path-
way.10 The [3,5]-rearrangements of esters are favored over the
more familiar [3,3]-rearrangement, both experimentally and
computationally. Since the imidates are isoelectronic with
esters, we undertook the DFT calculations to study the [3,3]-
and [3,5]-sigmatropic rearrangement of trichloroacetimidate 8.
Experimentally, we have shown above that the [3,5]-rearrange-
ment of 8 occurs, and the [3,5]-rearrangement of 22 is favored
over the [3,3]-rearrangement.
Figure 3 shows the calculated free energy (ΔG) profile at 450
°C (723.15K) for the [3,3]- and [3,5]-sigmatropic rearrange-
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ments of trichloroacetimidate 8 and for the subsequent
tautomerization to 10 and 12. The calculated barriers for
both rearrangements are similar (ΔG = 21.9 and 19.6 kcal/mol
for [3,3]-TS1 and [3,5]-TS2, respectively). While this energy
difference is below the computational accuracy of this level of
theory, it is consistent with the observation of 12 from the
pyrolysis of 19 and is in agreement with the experimental
preference for the [3,5]-rearrangement of the trimethyl imidate
22. It provides a reasonable mechanism for the formation of 10
from the 8. Interestingly, it seems to be the calculated entropies
of the two transition states ([3,3]-TS1 and [3,5]-TS2) that
favors the latter by 4.8 kcal/mol at 450 °C (TΔS), although the
former has a lower B3LYP electronic energy. The calculated
enthalpic corrections are less than 0.2 kcal/mol, favoring [3,5]-
TS2 as well. As expected, the amides 9 and 11 are significantly
more stable than the imidate 8, so subsequent equilibration is
not likely. An intramolecular pathway was calculated for the
tautomerization of 9 to 10. Analogously to what was calculated
in the case of ester rearrangements of 1,10 an intramolecular
transition state TS4 is found, connecting 9 to the aromatized
isomer 9′. This has only a modest barrier (ΔG = 28.4 kcal/
mol) from 9, so the reaction would be accessible under the
conditions for thermolysis of 19. A second intramolecular
transition state, TS5 leads to the observed product, 10. The
pathway through TS4 and TS5 provides an intramolecular
pathway for the formation of the stable amidophenol 10. An
intramolecular process from 11 to 11′ is not energetically
viable, so it is unlikely that the equally stable isomer 12 is
formed in the gas-phase pyrolysis of 8 (from 19). The direct
formation of 10, but not 12 could offer a speculative
explanation as to why 10, but not 12 is observed in the FVP
of 19. If the tautomers 11 (nonaromatic) or 11′ (zwitterionic)
were formed, each would be expected to be more reactive and
so would not survive for subsequent analysis. In summary, the
product distribution from 8 is calculated to be controlled by the
competition between the two unimolecular reactions via [3,3]-
TS1 and [3,5]-TS2 to ultimately give 10 as observed, and
possibly 12 (not observed).
Figure 4 shows the calculated geometries of 8 and of the
transition states. Although the trichloroacetimidate 8 was not
isolated, the calculated geometry shows that the imidate
nitrogen is over the dienone ring, positioned to bond to the
carbons for either the [3,3]- or [3,5]-rearrangement, but
slightly closer to the carbon involved in the [3,5]-rearrange-
ment.
The transition-state geometries for the rearrangements are
qualitatively similar to those calculated for the isolectronic ester
rearrangements of 1.10 Specifically, [3,3]-TS1 is a flattened boat
geometry, as was also calculated for ester rearrangement of 1 to
3. This geometry can be considered as resulting from state
mixing of two allowed transition states of the same symmetry:
(1) an all-π pericyclic one with (2) a pseudopericyclic one
where σ-bond breaking and forming would be in the plane of
the imidate. The breaking and forming bonds in [3,3]-TS1 are
relatively long, 2.10 and 2.42 Å, respectively. The subsequent
transition states TS3, TS4, and TS5 are all similar to the
isoelectronic ones calculated in the ester rearrangement
sequence.10
for a purely pseudopericyclic orbital topology. These
calculations are in qualitative agreement with the experiments,
in that the [3,3]- and [3,5]-rearrangements are calculated to
have similar barrier heights and the [3,5]-rearrangement
proceeds through a purely pseudopericyclic transition state.
The breaking and forming bonds (2.12 and 2.26 Å) are
calculated to be slightly shorter in [3,5]-TS2 than in [3,3]-TS1.
The ring-opened and ring-closed isomers 22 and 23 were
studied at the B3LYP/6-31G(d,p) level. Geometry optimiza-
tion gave a structure of 23 that was similar to the X-ray crystal
structure. At this admittedly approximate level, 22 was
calculated to be more stable (gas phase) than 23 by 2.9 kcal/
mol in the gas phase.
1
The ratio of 22 to 23 is solvent dependent by H NMR. To
estimate the effects of solvent polarity, single-point energy
calculations were performed on 22 and 23 using the SCRF-
PCM dielectric constant model for solvation.49 As the dielectric
constant increased from CCl4 to benzene-d6, to CDCl3, the
energetic preference for 23 decreased (see Table S1). This
trend is in accord with the NMR results in Table 2, even
though the calculated energy differences are not realistic. This
argues that the experimental trend in the equilibrium
distribution of 22 and 23 reflects the stabilization of 22 by
polar solvents. Acetone does not fit this trend, arguably because
of hydrogen bonding that is not reproduced in the dielectric
continuum model calculations.
CONCLUSIONS
■
The tetracyclic compound 19 has been synthesized and
characterized by X-ray crystallography and NMR. It may be a
thermal precursor to the trichloroimidate 8. Flash vacuum
pyrolysis of 19 led to a low yield of the trichloroacetamide
(10), presumably formed via a retro-Diels−Alder reaction to
give either 8 or 20 (in equilibrium), followed by a thermal
[3,5]-rearrangement of 8 to 9 and subsequent tautomerization
to 10. The product anticipated from [3,3]-rearrangement of 8
and subsequent tautomerization (12) was not observed.
The dienyl trichloroacetimidate 22 (in equilibrium with the
ring-closed isomer 23) has been synthesized and characterized
by NMR spectroscopy (and 23 by X-ray crystallography). Its
geometry is appropriate for either a [3,5]- or a [3,3]-
sigmatropic rearrangement, and indeed, 25 and 26 are the
major products observed upon FVP or thermolysis in benzene-
d6. The product (25) from the [3,5]-rearrangement is (slightly)
favored over the [3,3]-product (26) by a 2.3:1 ratio at 60 °C in
benzene-d6.
The [3,5]-rearrangements are geometrically prevented from
achieving a suprafacial/antarafacial transition state geometry
and so would be forbidden under the Woodward−Hoffmann
rules. They are orbital symmetry allowed with a pseudoper-
icyclic transition state orbital topology, however. This
qualitative analysis is supported by B3LYP/6-31G(d,p)
transition state calculations, which show a planar geometry
on the imidate in the calculated transition state for the [3,5]-
rearrangement, [3,5]-TS2. These results add an additional
example to the small number of experimental systems where
six-centered and eight-centered concerted reactions are
competitive because of the pseudopericyclic nature of the
transition states.
For the [3,5]-rearrangement, a suprafacial all-π transition
state would be forbidden, as discussed above, but the
pseudopericyclic one would be allowed. The calculated
transition state [3,5]-TS2 reflects this; the breaking and
forming σ-bonds are in the plane of the imidate, as expected
EXPERIMENTAL SECTION
General Experimental Information. All reactions were carried
out in oven-dried glassware under an inert atmosphere of dry nitrogen.
■
G
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All solvents and reagents were obtained from commercial sources and
5.55 (m, 1H), 5.40−5.38 (m, 1H), 3.31 (bs, 1H), 3.01−2.96 (m, 3H),
2.77−2.70 (m, 1H), 2.53−2.46 (m, 1H), 1.94−1.88 (m, 1H), 1.36 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 162.2, 132.7, 132.0, 131.5,
129.2, 101.4, 95.5, 48.1, 47.2, 45.2, 38.6, 32.5, 21.4.
1
used without further purification unless otherwise specified. H and
13C NMR spectra were measured on 400 MHz spectrometers. High-
resolution mass spectrometry (HRMS) was performed under positive-
mode electrospray ionization (ES) conditions. GC data were obtained
on a capillary column with FID or MS detection, and integrations are
uncorrected. Melting points were measured on a capillary melting
point apparatus and are uncorrected.
Synthesis of 6-Hydroxy-3,5,6-trimethylcyclohexa-2,4-dienone 21.
Compound 21 was synthesized from 2,3,5-trimethylphenol (1.0 g, 7.4
mmol) according to the procedure described in literature.42 This gave
21 (446 mg, 40%) as a yellow-colored low-melting crystalline solid.
1
The H NMR and 13C NMR of 21 agreed with those reported in
General Procedure for Flash Vacuum Pyrolysis. The FVP of
19 and 23 was carried out on recrystallized solid samples. The
compound to be pyrolyzed (19 or 23) was transferred into a quartz
tube (65 cm long and 2 cm diameter) either directly as solid crystals or
as a solution in diethyl ether (23) or acetone (19; due to its better
solubility in acetone). The solvent was evaporated, and the compound
was dried under high vacuum followed by purging the tube with
nitrogen gas. The quartz tube was connected to a U-shaped product
trap that was cooled with liquid nitrogen, and the entire setup was kept
under vacuum (0.01 mmHg). The end of the quartz tube bearing the
sample was initially placed outside the circular furnace and when the
temperature of the furnace reached the desired temperature for
pyrolysis the quartz tube was gradually moved through the hot zone of
quartz tube maintained at a specific temperature (ranging from 300 to
500 °C). The temperature was recorded using a thermocouple that
was held in place using a custom-made holder to ensure
reproducibility of results. The rearranged product mixture was
collected at the cooler region at the end of the quartz tube. More
volatile components were trapped in the U-shaped product trap cooled
under liquid nitrogen bath. The rearranged product mixture was
collected from the quartz tube and U-shaped tube by dissolving in
dichloromethane. The samples were then analyzed by 1H NMR, GC−
MS, and GC−FID and by comparison to authentic materials.
Synthesis and Characterization of Substrates. 9-Methyl-8-
oxo-3a,4,7,7a-tetrahydro-3H-4,7-ethanoinden-9-yl Acetate 16.
Compound 16 was synthesized from 1 (1.0 g, 6.0 mmol) according
to the procedure described in the literature.50 The compound was
purified by column chromatography to yield 16 as a white solid (1.0 g,
72%): 1H NMR (400 MHz, CDCl3) δ 6.26 (t, J = 7.3 Hz, 1H), 6.06 (t,
J = 7.1 Hz, 1H), 5.68−5.66 (m, 1H), 5.43−5.42 (m, 1H), 3.90−3.88
(m, 1H), 3.27−3.25 (m, 1H), 3.20−3.18 (m, 1H), 2.75−2.69 (m, 1H),
2.56−2.49 (m, 1H), 2.06 (s, 1H), 1.99−1.95 (m, 1H),1.53 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 206.3, 170.2, 133.9, 133.5, 129.9,
literature.42,43
Synthesis of 1,2,4-Trimethyl-6-oxocyclohexa-2,4-dien-1-yl 2,2,2-
trichloroacetimidate (22) and 5,7,7a-Trimethyl-2-(trichloromethyl)-
3a,7a-dihydrobenzo[d]oxazol-3a-ol (23). To a suspension of sodium
hydride (∼27 mg, 1.05 mmol, 95% w/w) in dry THF (3 mL) was
added a solution of starting alcohol 21 (200 mg, 1.32 mmol) in dry
THF (2 mL) at −20 °C, and the mixture was allowed to stir at −20 °C
for about 30 min. Trichloroacetonitrile (198 μL, 1.97 mmol) was then
added to the mixture dropwise, and the resulting mixture was stirred at
−20 °C for about 30 min. The reaction was monitored by removing
small aliquots for 1H NMR spectroscopy. Upon completion, the
reaction was quenched with ammonium chloride solution, THF was
evaporated, and the aqueous layer was extracted with three 10 mL
portion of ethyl acetate. The organic layer was then washed with brine,
dried over anhydrous sodium sulfate, and concentrated using a
rotavap. The resulting residue was purified by column chromatography
(silica gel, 15% ethyl acetate in hexane) to yield the desired compound
as a yellow gummy solid. The compound was crystallized in ether/
pentane solvent system to yield colorless crystals (246 mg, 63%) of 23,
which equilibrates with 22 in solution as indicated by 1H NMR studies
in CCl4, benzene-d6, CDCl3 and acetone-d6. These crystals were
suitable for X-ray diffraction studies.
Note: Side product 24 was obtained when 1.5 equiv of
trichloroacetonitrile was used.44 We were able to avoid the formation
of 24 by adding only 1 equiv of trichloroacetonitrile.
1H NMR of 22 and 23 in CCl4 as read from an equilibrated mixture
1
of 22 and 23: H NMR of the major isomer 23 (72%) (400 MHz,
CCl4) 5.62 (s, 1H), 5.57 (bt, J = 1.4 Hz, 1H), 5.11 (bs,1H), 1.96 (s,
1
3H), 1.84 (s, 3H), 1.66 (s, 3H); H NMR of the minor isomer 22
(28%) 8.23 (bs, 1H), 5.88 (s, 2H, 2 −CH), 2.09 (s, 3H), 1.95 (s, 3H),
1.50 (s, 3H).
1
1H NMR of 22 and 23 in CDCl3 in an equilibrated mixture: H
NMR of the major isomer 22 (69%) (400 MHz, CDCl3) δ 8.35 (s,
1H), 5.99 (s,1H), 5.97 (s, 1H), 2.07 (s, 3H), 1.94 (s, 3H), 1.52 (s,
3H); 1H NMR of the minor isomer 23 (31%) δ 5.57 (s, 1H), 5.54 (s,
1H), 2.99 (s, 1H), 1.91 (s, 3H), 1.78 (s, 3H), 1.64 (s, 3H); 13C NMR
of the mixture of 22 and 23 (100 MHz, CDCl3) δ 197.9, 165.2, 159.7,
153.7, 151.7, 136.1, 133.4, 124.7, 123.5, 122.1, 120.9, 96.9, 94.7, 90.76,
84.19, 24.79, 23.17, 21.51, 17.52, 17.48, 16.90.
128.8, 81.1, 51.3, 49.4, 45.6, 38.6, 34.2, 22.0, 21.4.
Compound 17 was synthesized from 16 (600 mg, 2.6 mmol)
according to the procedure described in literature50 to yield the
1
desired alcohol as a white solid (437 mg, 89%): H NMR (400 MHz,
CDCl3) δ 6.29 (t, J = 7.3 Hz, 1H), 6.02 (t, J = 7.4 Hz, 1H), 5.67 (m,
1H), 5.42 (m, 1H), 3.21−3.16 (m, 3H), 2.98−2.96 (m, 1H), 2.57−
2.52(m, 2H), 1.98−1.94 (m, 1H), 1.29 (s, 3H) [the literature 1H
NMR data seems inconsistent with the structure; lit.50 1H NMR
(CDCl3) δ 1.28 (3H, s), 5.36−5.50 (1H, m), 5.64−5.76 (1H, m), 6.04
(1H, dt, J = 7, 1 Hz), 6.32 (1H, dt, J = 7, 1 Hz); the literature
elemental analysis is consistent with the structure]; 13C NMR (100
MHz, CDCl3) δ 214.7, 133.9, 133.7, 130.0, 128.1, 73.2, 51.7, 51.0,
49.2, 38.5, 33.5, 26.2.
8a-Methyl-2-(trichloromethyl)-4,4a,7,7a,8,8a-hexahydro-3aH-
4,8-ethenoindeno[5,6-d]oxazol-3a-ol 19. To a solution of alcohol 17
(100 mg, 0.53 mmol) in dichloromethane (∼10 mL) was added DBU
(∼16 μL, 0.11 mmol) dropwise at 0 °C. The mixture was allowed to
stir at 0 °C for about 20 min, and then trichloroacetonitrile (∼58.0 μL,
0.578 mmol) was added to the mixture at 0 °C. The reaction mixture
turned reddish brown in color. The reaction was then allowed to stir at
room temperature for about 1 h. The TLC showed the disappearance
of alcohol 17. The solvent was evaporated under reduced pressure to
yield a brown oil. The brown residue was purified by column
chromatography, and the compound was crystallized in ethanol to
yield colorless crystals of 19 (130 mg, 74%, mp 248−250 °C) which
were used for X-ray diffraction studies.
1H NMR of 22 and 23 in benzene-d6 in an equilibrated mixture: 1H
NMR of the major isomer 23 (63%) (400 MHz, C6D6) δ 5.74(s, 1H),
5.17 (s, 1H), 4.65 (s, 1H), 1.69 (s, 3H), 1.68 (s, 3H), 1.43 (s, 3H); 1H
NMR of the minor isomer 22 (37%) 8.28 (s, 1H), 5.99 (s, 1H), 5.45
1
(s, 1H), 1.69 (s, 3H), 1.43 (s, 3H), 1.36 (s, 3H); H NMR of 23
(100%) in acetone-d6 (400 MHz, CD3COCD3) δ 5.59 (s, 1H), 5.51
(bs, 1H), 5.49 (s, 1H), 1.87, (s, 3H), 1.73 (s, 3H), 1.57 (s, 3H).
Compound 24 was obtained (70 mg, 16%) as a less polar impurity
formed in the above reaction starting from 200 mg of 21. It is a
colorless crystalline solid (mp 74−76 °C). The structure of 24 was
confirmed by X-ray crystallography. The 1H and 13C NMR spectra are
1
in accord with this structure: H NMR (400 MHz, CDCl3) δ 6.18 (s,
1H), 4.63 (s, 1H), 2.16 (s, 3H), 1.76 (s, 3H), 1.57 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 189.9, 162.4, 158.4, 128.0, 90.0, 86.0, 75.0, 59.2,
22.8, 21.8, 17.3.
2,2,2-Trichloro-N-(2-hydroxy-3-methylphenyl)acetamide 10. As
shown in Scheme S1 (Supporting Information), compound 10 was
synthesized in three steps. Nitration of o-cresol with HNO3/AcOH
yielded 6-nitro-o-cresol.51 This (200 mg) was reduced using H2 and
10% Pd/C to yield the corresponding amino phenol (143 mg, 89%).51
The aminophenol (80 mg, 0.65 mmol) was then treated with
hexachloroacetone in hexane and the reaction mixture was refluxed for
Note: The above reaction was also repeated using 200 mg of 17 and
KH as a base, and we obtained 285 mg (81%) of similar quality
1
crystals: H NMR (400 MHz, CDCl3) δ 6.23−6.15 (m, 2H), 5.57−
H
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The Journal of Organic Chemistry
Article
6 h, to yield the desired trichloroacetamide 10 as a white solid (141.06
mg, 86%):52 1H NMR (400 MHz, CDCl3) δ 8.94 (bs, 1H), 7.71 (d, J
= 6.8 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 5.72
(bs, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.9, 144.9,
128.3, 125.4, 124.4, 121.3, 119.2, 92.17, 29.8,16.0; EIMS m/z (relative
abundance) 269 (4), 267 (4), 150 (100), 122 (24); HRMS (ESI) calcd
for [C9H8Cl3NO2 + H]+ 267.9693 found 267.9688.
followed by brine, and then dried over sodium sulfate. It was then
filtered and concentrated to yield a red/brown solid that was purified
by column chromatography to yield 33 as a pale brown solid (129.7
mg, 78%, mp 149−151 °C). Note: The above reduction did not work
with H2 (balloon) and 10% Pd/C at room temperature; hence, we
reduced the nitro compound using NaBH4/MeOH and 10% Pd/C:
1H NMR (400 MHz, CDCl3) δ 6.44 (s, 1H), 4.33 (bs, 1H), 3.33 (bs,
2H), 2.17 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 146.2, 136.2, 122.5, 120.8, 120.5, 114.8, 17.8, 13.7, 12.2; MS
(EI) m/z 151, 136, 106, 91; EIMS m/z (relative abundance) 152 (10),
151 (100), 136 (65), 106 (62), 91 (38), 77 (40); HRMS (ESI) calcd
for [C9H13NO + H]+ 152.1075 found 152.1069.
2,2,2-Trichloro-N-(4-hydroxy-3-methylphenyl)acetamide 12
(Scheme S1, Supporting Information). Compound 12 was
synthesized by treating commercially available 4-amino-o-cresol (100
mg, 0.812 mmol) with hexachloroacetone in hexane at 65−70 °C for
about 4 h52 and was obtained as a white solid (189 mg, 92%): H
1
NMR (400 MHz, CDCl3) δ 8.20 (bs, 1H), 7.33 (d, J = 2.6 Hz, 1H),
7.28 (d, J = 2.8 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 4.77 (bs, 1H), 2.27
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 152.1, 128.9, 125.0,
123.8, 119.9, 115.5, 93.0, 16.0; EIMS m/z (relative abundance)
271(6), 269 (18), 267 (18), 150 (30), 122 (100). Anal. Calcd for
C9H8Cl3NO2: C, 40.26; H, 3.00; N, 5.22. Found: C, 40.14; H, 2.75; N,
5.15.
2,2,2-Trichloro-N-(4-hydroxy-2,3,6-trimethylphenyl)acetamide
26. To a solution of 29 (100 mg, 0.66 mmol) in dichloromethane was
added trichloroacetic anhydride (133 μL, 0.73 mmol) at 0 °C, and the
mixture was allowed to stir at room temperature under N2 for 3 h. The
reaction was monitored by TLC. Upon completion of reaction, the
solvent was evaporated, and the residue was purified by column
chromatography to yield the desired 26 as a pale yellow solid (180 mg,
1
92%; mp 216−218 °C; the compound turned brown at 180 °C): H
Compounds 30, 31, 32, 33, 25, and 26 were synthesized as
described in Scheme S2 (Supporting Information).
NMR (400 MHz, CDCl3, sparingly soluble) δ 7.87 (bs, 1H), 6.44 (s,
1
1H), 2.16 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H); H NMR (400 MHz,
Synthesis of 2,3,5-Trimethyl-6-nitrophenol (30) and 2,3,5-
Trimethyl-4-nitrophenol (31). 2,3,5-Trimethylphenol (5.0 g, 37
mmol was nitrated as described in the literature.53 1H and 13C NMR
spectra of 30 (2.2 g, 33%) were in agreement with the literature.54 The
authors reported but did not isolate the minor product 31; however,
we were able to isolate 31 as a yellow crystalline solid (1.8 g, 27%, mp
79−81 °C) and characterized it by 1H and 13C NMR: 1H NMR of 31
(400 MHz, CDCl3) δ 6.50 (s, 1H), 5.48 (bs, 1H), 2.21 (s, 3H), 2.17
(s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.5, 146.6,
130.3, 128.2, 121.9, 114.6, 17.5, 15.1, 11.8; EIMS m/z (% relative
abundance) 181 (100), 164 (76), 91 (82), 79 (36).
C6D6) δ 6.94 (bs, 1H), 5.99 (s, 1H), 2.01 (s, 3H), 1.94 (s, 3H), 1.89
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.1, 153.6, 135.8, 133.6,
124.4, 121.5, 114.8, 93.0, 18.0, 14.8, 12.1; EIMS m/z (relative
abundance) 299 (2), 297 (6), 295 (6), 178 (32), 150 (100), 117 (24),
107 (36), 91 (42), 77(65); HRMS (ESI) calcd for [C11H12Cl3NO2 +
H]+ 296.0006, found 296.0000.
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthesis of 2-Amino-3,5,6-trimethylphenol 32.55 To a solution
of 30 (160 mg, 0.88 mmol) in THF (∼5 mL) was added 10% Pd/C
(∼16 mg, 0.088 mmol) at room temperature, and the mixture was
allowed to stir under H2 atmosphere (H2 balloon) for about 6 h. The
TLC showed the appearance of a more polar spot (20% ethyl acetate/
hexane). The reaction mixture was poured over a bed of Celite, which
was washed with ethyl acetate (3 × 5 mL). The filtrate was then
concentrated and dried under high vacuum pump to yield the desired
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01355.
Synthetic schemes for the preparation of authentic
standards 10, 12, 25, and 26, GC conditions, a
representative GC trace and 1H NMR spectrum of
1
pyrolysis products, H and 13C NMR spectra of all new
compounds, and computational information, including
energies, pictures, and Cartesian coordinates of all
conformations of all calculated structures(PDF)
X-ray crystallographic data (CIF)
1
amine as an off-white solid (134 mg, 90%): H NMR (400 MHz,
CDCl3) δ 6.53 (s, 1H), 3.57 (bs, 2H), 2.18 (s, 3H), 2.17 (s, 3H), 2.13
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 129.4, 128.7, 123.6,
123.3, 119.6, 19.6, 17.3, 11.9; EIMS m/z (relative abundance) 152
(10), 151 (100), 136 (60), 106 (22), 91 (20).
2,2,2-Trichloro-N-(2-hydroxy-3,4,6-trimethylphenyl)acetamide
25. Compound 25 was synthesized according to the general procedure
described in the literature52 The aminophenol 32 (150 mg, 0.99
mmol) was taken up in hexane, and hexachloroacetone (166 μL, 1.09
mmol) was added to it at room temperature. The mixture was then
heated at 65−70 °C for about 6 h. TLC showed the disappearance of
the starting aminophenol 32 and formation of a new less polar spot.
The solvent was evaporated, and the residue was purified by column
chromatography to yield 25 as an off-white solid (132 mg, 45%, mp
150−152 °C): 1H NMR (400 MHz, CDCl3) δ 8.25 (bs, 1H), 6.66 (s,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: david.birney@ttu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
We gratefully acknowledge generous support from the Robert
A. Welch Foundation (Grant No. D-1239). We also are grateful
for the use of a 400 MHz MNH spectrometer made available
through the NSF (CRIF MU Grant No. CHE-1048553) and
access to the Robinson cluster which is funded by a CRIF MU
instrumentation grant (CHE-0840493) from the National
Science Foundation. Both instruments are in the Department
of Chemistry and Biochemistry, Texas Tech University. We
thank Mr. David Purkiss for assistance with the NMR spectra,
Dr. Kazimierz Surowiec and Dr. Yehia Mechref for assistance
with mass spectrometry, Professor David Lemal for inspiration
and encouragement for our ongoing studies of pseudopericyclic
1H), 6.38 (s, 1H), 2.24 (s, 6H), 2.18 (s, 3H); H NMR (400 MHz,
C6D6) δ 7.53 (bs, 1H), 6.62 (s, 1H), 6.41 (s, 1H), 2.12 (s, 3H), 2.01
(s, 3H), 1.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.4, 148.5,
137.7, 129.3, 124.7, 124.3, 119.8, 92.3, 20.1, 17.7, 12.1; EIMS m/z
(relative abundance) 297 (4), 295 (4), 178 (100), 150 (14); HRMS
(ESI) calcd for [C11H12Cl3NO2 + H]+ 296.0012 found 296.0004.
4-Amino-2,3,5-trimethylphenol 33.56 Compound 33 was synthe-
sized according to the general procedure described in the literature.57
To a solution of 31 (200 mg, 1.1 mmol) in methanol at 0 °C was
added 10% Pd/C (0.1 mmol). Then a solution of NaBH4 (125 mg,
3.31 mmol) in water (∼2 mL) was added dropwise to the above
solution. The reaction mixture was allowed to stir at room temperature
for about 30 min. The TLC showed the formation of a new more polar
spot. The mixture was filtered through a Celite bed, and the Celite bed
was washed with ethyl acetate. The filtrate was treated with water,
́
reactions, and Professor Stephane Quideau for introducing us
to the rearrangement chemistry of acetoxycyclohexadienones.
I
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apart for the rearrangements to occur. Rajale, T.; Sharma, S.; Stroud,
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(36) Metlesics, W.; Wessely, F. Monatsh. Chem. 1957, 88, 108−117.
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(38) Adler, E.; Holmberg, K. Acta Chem. Scand. 1971, 25, 2775−
2776.
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