Studies on the Himbert intramolecular arene/allene diels-alder cycloaddition. Mechanistic studies and expansion of scope to all-carbon tethers

Article abstract of DOI:10.1021/ja4025963

The unusual intramolecular arene/allene cycloaddition described 30 years ago by Himbert permits rapid access to strained polycyclic compounds that offer great potential for the synthesis of complex scaffolds. To more fully understand the mechanism of this

Full text of DOI:10.1021/ja4025963

Article
pubs.acs.org/JACS
Studies on the Himbert Intramolecular Arene/Allene Diels−Alder
Cycloaddition. Mechanistic Studies and Expansion of Scope to All-
Carbon Tethers
Yvonne Schmidt,†,‡ Jonathan K. Lam,†,‡ Hung V. Pham,†,§ K. N. Houk,*,§
and Christopher D. Vanderwal*,‡
‡1102 Natural Sciences II, Department of Chemistry, University of California-Irvine, Irvine, California, 92697-2025, United States
§Department of Chemistry and Biochemistry, University of California-Los Angeles, 607 Charles E. Young Drive, Los Angeles,
California 90095-1569, United States
S
* Supporting Information
ABSTRACT: The unusual intramolecular arene/allene cyclo-
addition described 30 years ago by Himbert permits rapid
access to strained polycyclic compounds that offer great
potential for the synthesis of complex scaffolds. To more fully
understand the mechanism of this cycloaddition reaction, and
to guide efforts to extend its scope to new substrates, quantum
mechanical computational methods were employed in concert
with laboratory experiments. These studies indicated that the
cycloadditions likely proceed via concerted processes; a
stepwise biradical mechanism was shown to be higher in energy in the cases studied. The original Himbert cycloaddition
chemistry is also extended from heterocyclic to carbocyclic systems, with computational guidance used to predict
thermodynamically favorable cases. Complex polycyclic scaffolds result from the combination of the cycloaddition and
subsequent ring-rearrangement metathesis reactions.
expansion of scope to include carbocyclic products that
required key computational insights for success.
INTRODUCTION
■
The unusual intramolecular arene/allene cycloaddition reaction
reported over 30 years ago by Himbert and Henn1,2 (eq 1)
BACKGROUND
■
Our recent work on the metathesis rearrangement of Himbert
cycloadducts3 (Scheme 1) points to the utility of this
fascinating cycloaddition reaction in strategies to rapidly access
complexity from simple substrates. That work represents the
first of many applications of this reaction that we are interested
in pursuing. As a result, a greater understanding of the
mechanism of this dearomatizing intramolecular Diels−Alder
(IMDA) cycloaddition, which will provide better predictability
in reaction outcome, is critical to our ongoing studies.
converts relatively simple reactants into complex bridged
polycyclic architectures that are themselves poised for further
transformations. In what appears to be the first application of
this chemistry, our UC Irvine laboratory used lactam-containing
Himbert cycloadducts as the substrates for ring-rearrangement
metathesis reactions, resulting in fused polycyclic lactams.3 This
chemistry is part of our broader program to take advantage of
under-utilized processes to convert readily available aromatic
systems into complex organic scaffolds.4 In past cases when
mechanistic details have been difficult to glean from experi-
ment, our UC Irvine and UC Los Angeles laboratories have
engaged in fruitful collaborations involving density functional
theory (DFT) methods to provide useful insights into
mechanism.5 In this disclosure, we report our joint investigation
of some mechanistic aspects of the fascinating dearomatizing
cycloaddition first described by the Himbert group, and an
Himbert and co-workers were the first to discover and study
the scope of the intramolecular arene/allene cycloaddition
reactions;1,2 and on the basis of the relative insensitivity of
cycloaddition rates to donor and acceptor groups on the arene
in amide-tethered substrates, they were led to favor a concerted
cycloaddition mechanism over a polar, stepwise alternative.6
Trifonov and Orahovats studied closely related cycloadditions
that were set up by the reaction of allenoic acids with N-
arylcarbodiimides (eq 2).7 After activated ester formation and
O- to N-acyl transfer, a spontaneous cycloaddition of the in situ
generated allene carboximide (8) ensued at ambient temper-
Received: March 18, 2013
© XXXX American Chemical Society
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cycloaddition in the reactions studied by Himbert, the
experiments of Orahovats do point to the possibility of a
stepwise radical pathway. However, it should be noted that this
specific system differed from most of the reactions studied by
Himbert by the presence of the N-acylurea and, more
importantly, the γ-phenyl substituent on the allene.
Scheme 1. Ring-Rearrangement Metathesis of Himbert
Cycloadducts to Access Complex Polycyclic Lactams
As noted by Orahovats and Trifonov,7 molecular models
indicate that close proximity and excellent alignment of the sp-
hybridized allene carbon with the ipso carbon of the arene ring
is easy to attain in these cycloaddition substrates; on the other
hand, the distal carbons of each reacting π-system are not
subject to such a perfect arrangement. This situation lends itself
to the idea that five-membered ring formationleading to a
diradical intermediate of type 11 (eq 3)might be a
mechanistically relevant first step. Recombination of the
pentadienyl radical and the alkyl radical on the γ-carbon of
the former allene would complete the formal cycloaddition
process. The intermediacy of spiro-fused biradical 11 provides a
means for loss of enantioenrichment via rotation about the
former allene Cβ−Cγ σ bond. Certainly, a key consideration for
the stepwise radical mechanism is the stability of the partially
cyclized biradical intermediate. Appropriate substituents
present on the allene γ-carbon can offer significant stabilization
to the resulting radical, which does not benefit immediately
from allylic stabilization owing to orbital orthogonality.
To learn more about the underlying cycloaddition
mechanism in both of the Himbert and Orahovats systems,
we studied the energetics of the two likely mechanisms using
DFT. Furthermore, we investigated the Himbert case
experimentally using both stereochemical probes and substrates
designed to detect radical behavior.
Cycloaddition of Allene Carboxanilides. Beginning with
the Himbert reaction of the type shown in eqs 1 and 3, both the
concerted and the stepwise radical mechanisms were
investigated. All stationary point structures were optimized
using the B3LYP8 functional and 6-31G(d) basis set in
Gaussian09.9 Single-point calculations on closed-shell species
were conducted with M06-2X/6-311+G(d,p) on the B3LYP
optimized geometries. In general, B3LYP and M06-2X produce
similar optimized geometries.10 However, activation energies
and reaction energies as predicted by the two methods are
different; as we have extensively benchmarked for cyclo-
additions such as those studied here,10a B3LYP is known to
overestimate barriers by ∼5 kcal/mol for concerted processes
but provide sufficiently accurate values for reactions leading to
diradicals. Additionally, the energies of cycloaddition reactions
are predicted by B3LYP to be ∼10 kcal/mol less exothermic
than experiment.11 We have found that M06-2X single-point
calculations with reasonably large basis sets give much better
values.
ature. In contemplating a possible stepwise mechanism, they
began with chiral, nonracemic allenoic acid 7, and subjected it
to reaction with a variety of carbodiimides (only one example
shown). In all cases, a significant loss of enantiomeric purity
was observed, and reasonable control experiments to ensure
that the allenoic acid had not racemized prior to reaction were
performed. Keeping in mind the results of Himbert that argued
against a stepwise polar pathway, they suggested that a stepwise
radical mechanism would account for all of the data that was
available to them (see below).7
We posited that a greater comprehension of the reaction
mechanism across various substrate types would inform on
which, if any, cycloadditions would proceed with high levels of
conservation of enantiomeric purity. The ability to transfer
allenic axial chirality to point chirality would be critical to some
applications of this chemistry in the synthesis of enantiopure
complex molecules, including natural products and scaffolds for
medicinal chemistry. Furthermore, such an improved mecha-
nistic understanding might facilitate the expansion of scope to
systems with different tethers. In the first portion of this
disclosure, we present a computational investigation of both the
Himbert cycloaddition of allene carboxamides and the
Orahovats variant, as well as supporting experimental results.
In the second part, we document the previously unknown
cycloaddition reactions of benzyl allenyl ketones and show how
computation provides a reliable predictive tool for these
reactions.
RESULTS AND DISCUSSION
■
Cycloaddition Mechanism. The relatively narrow range of
cycloaddition rates noted by Himbert among substrates with a
broad range of electronically different arenes6 (also observed in
our studies) effectively militates against a polar stepwise
mechanism. While there are no reported experimental
observations that explicitly reject the notion of a concerted
The M06-2X functional has been shown to provide accurate
reaction energies and enthalpies for C−C bond formation, but
has proven problematic for open-shell species.12 We consider
the M06-2X results to be most reliable for the concerted
process; the relative energies of B3LYP open-shell (diradical)
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Figure 1. Calculated energies for the stepwise and direct cycloaddition of arene/allene 13, with transition structure geometries shown below. All
energies shown are in kcal/mol from M06-2X/6-311+G(d,p)/CPCM(xylenes) single-point calculations on geometries optimized with B3LYP/6-
31G(d). “TS”Di_14−15 (in red) was estimated by constraining the lactam C−C σ bond to 1.58 Å. (B3LYP energies are shown in parentheses).
and closed-shell species are more reliable. Thus, the difference
is used to phase the energetics of diradical species. We refer to
the latter as corrected M06-2X energies. All energies by both
methods are given in the Supporting Information. Vibrational
frequencies were computed to determine the nature of each
stationary point; local minima and transition structures showed
0 and 1 imaginary frequency, respectively. The conductorlike
polarizable continuum model (CPCM)13 was used to compute
solvation energies.
TS_13−15, and the formation of the diradical, TSDi_13−14,
are essentially isoenergetic, suggesting competition of both
pathways. The formation of 15 is exergonic by 2.0 kcal/mol
(M06-2X). B3LYP calculations suggest that this reaction is
endergonic by 9.2 kcal/mol but, as alluded to earlier, this
method is known to underestimate the exergonicity of
cycloadditions.11 The stepwise pathway initially leads to
diradical intermediate 14, which is 20.4 kcal/mol higher than
the starting material. In this intermediate, the pentadienyl
radical is extensively stabilized, but the other secondary radical
does not initially benefit from allylic stabilization owing to the
orthogonality of orbitals. From 14, radical recombination with
The reaction coordinate diagrams for both the concerted and
stepwise mechanisms are shown in Figure 1. For the reaction
13 → 15, the transition structures for the concerted reaction,
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the para carbon of the phenyl ring again yields 15. The
transition structure for the second step, TSDi_14−15, could
not be located on the potential energy surface; all efforts
resulted in the concerted transition structure or led directly to
ring-closure. In order to estimate the free energy value for this
process, the C−C bond formed in the previous step was
constrained to a value of 1.58 Å, slightly longer than its value of
1.55 Å in intermediate 14. This process yielded an energy value
for “TS”Di_14−15 of about 37.8 kcal/mol, making it the rate-
determining step of the stepwise reaction. Reversion of the
diradical to reactants and subsequent concerted cycloaddition
will be faster than ring-closure to the cycloadduct.
The transition state for the concerted and stepwise pathways
have virtually identical energies; conceivably, a single transition
state actually leads to both 15 and diradical 14. This situation
would require a bifurcation of the downhill pathway from
TS_13−15, and related bifurcations have been found in ketene-
diene cycloadditions.14
The energy barrier to cyclization to afford the formal [2 + 2]
cycloaddition product 16 has a ΔG⧧ of 37.2 kcal/mol, similar to
that for ring-closure to observed product 15. However, 16 is
substantially unfavorable thermodynamically and would, if
formed at all, reform diradical 14 and proceed either toward
initial allene 13 or the more stable product 15. This conclusion
is consistent with the failure to observe product 16
experimentally.
The optimized transition structures for the intramolecular
cycloaddition of allenecarboxamide 13 are also shown in Figure
1. The concerted transition structure TS_13−15 is slightly
asynchronous, with forming-bond lengths of 2.0 Å and 2.3 Å.
The diradical transition structure TSDi_13−14 is relatively
late, as indicated by the short C−C forming-bond length of
1.88 Å. By contrast, the two diradical-closing transition
structures “TS”Di_14−15 and TSDi_14−16 are early,
demonstrating longer bond lengths typical of radical recombi-
nations.
The reaction is carried out at 170 °C and is nearly
thermoneutral. Therefore, the reaction should be reversible
and under thermodynamic control. An exergonicity of only 2.0
kcal/mol is consistent with the observed 74% yield of 15. The
computed equilibrium constant, [15]/[13] = 9.7. By examining
the calculated thermodynamic energies of the reactants and
products, the outcome of this reaction, as well as those of
related analogs, can be predicted (see below).
These results predict that this particular Himbert cyclo-
addition proceeds via a concerted pathway, but that a single
reversible cyclization to form diradical intermediate 14 is
competitive with the direct Diels−Alder process. As a result, it
might be possible to racemize chiral, enantioenriched allenes via
diradicals of type 14, even while the only productive pathway is
via the concerted cycloaddition, a reaction that would be
expected to be stereospecific. We have performed experiments,
analogous to those of Orahovats and Trifonov, to test the idea
that such a racemization pathway might occur (Figure 2a).
Racemic N-methyl allenecarboxanilide 18 was prepared by
Wittig reaction of the precursor phosphorane 17 with in situ
generated methylketene as described by Himbert,15 and it was
resolved by semipreparative HPLC using chiral solid supports
to obtain (−)-18 and (+)-18, each of greater than 99:1 er.16 At
this stage, the absolute configuration of these enantiomeric
allenes is unknown. Representative experiments shown in the
table of Figure 2 revealed that our hypothesisthat
racemization might be competitive with stereospecific cyclo-
Figure 2. (a) Cycloaddition studies on enantiomerically enriched
allene 18. (b) Racemization studies on enantiomerically enriched
cycloadduct (+)-19.
additionappears to be correct. When enantiomerically
enriched 18 was heated to 170 °C, conversion was nearly
complete after 4 h, affording cycloadduct 19 in 80:20 er.
Further experiments revealed a time-dependent decrease in
enantiopurity of the product, such that after 24 h the product
was isolated with a 64:36 er and in low yield owing to thermal
decomposition. However, running the reaction at 140 °C led to
product formation with reasonable conservation of enantiose-
lectivity. Therefore, the apparent competition between partial
cyclization/allene racemization and direct stereospecific cyclo-
addition is worthy of concern, but the use of the minimal
temperatures needed to promote cycloaddition can lead to
products with useful levels of enantioenrichment.
We presumed that loss of enantioenrichment over time
occurs in part via reversible cycloaddition with racemization of
the allene via radical spirocyclization (also reversible). To test
this idea, we investigated the thermal racemization of
enantioenriched cycloadduct (Figure 2b), also obtained by
semipreparative HPLC on chiral solid support. Heating of
enantioenriched cycloadduct (+)-19 to 170 °C for 10 h led to a
slight erosion of enantiopurity (from ≥99:1 to 90:10 er),
whereas heating to 140 °C for the same time led to recovery of
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enantiopure material. All of this data points to a concerted
cycloaddition that is readily reversible given enough thermal
energy, and the idea that racemization occurs by reversible
spirocyclization via a radical process appears reasonable. Of
course, other means of allene racemization cannot be
completely ruled out, but the neutral conditions in this case
make racemization via acid−base chemistry or reversible
nucleophilic attack to the allene unlikely. Furthermore, in
reactions that did not proceed to complete conversion,
recovered allene was still highly enantioenriched (96:4 er at
140 °C, 88:12 er at 170 °C).
Most importantly, we have shown that there is the possibility
of these Himbert cycloadditions proceeding with a significant
axial to central chirality transfer. The degree to which
enantiopurity is conserved will likely be influenced by the
radical stabilizing ability of the allene γ-substituent, and
certainly by the reaction temperature.
assumed that the methylene spacer insulating the thioether
from the allene in the presumed cycloaddition precursor would
reduce any serious steric or electronic impact of this group. We
hypothesized that, if the radical mechanism were operative,
expulsion of phenylthiyl radical from an intermediate like 26
followed by radical recombination would lead to spirocyclic
products related to 28. When 22 was heated to 140 °C, we
obtained a 1:1.7 ratio of cycloadduct 24 to diene 25 (E:Z
mixture), whose origin is most easily explained by the radical
cascade that we had predicted, followed by elimination of the
amide to restore aromaticity. At 170 °C, rearranged diene 25
was the only identifiable product. We believe that the outcome
of these experiments further supports the potential competition
of radical-based reactions in these Himbert cycloadditions, and
opens up possibilities to engineer intriguing new reactions
based on the relatively facile formation of diradical
intermediates of type 26.
For probes to detect the intermediacy of radical
intermediates, we considered cyclopropane- and phenyl-
thiomethyl-bearing allenes. Generation of γ-cyclopropyl-sub-
stituted allene 21 and γ-thiophenylmethyl allene 22 (Scheme 2)
Cycloaddition of Allenic Imides. We have also computa-
tionally examined the substrate used by Orahovats.7 Urea 8,
formed in situ as shown in eq 2, undergoes cycloaddition to
form 9 at ambient temperatures. The key differences present in
9 and the Himbert substrate 13 are the N-acylurea group,
which is able to engage in intramolecular hydrogen bonding,
the methyl group on the allene α-carbon, and the phenyl
substituent on the allene γ-carbon (in place of the methyl
substituent in 13). The concerted and stepwise cycloaddition
pathways of 29, a model for imide 8 wherein the cyclohexyl
substituent has been replaced with a methyl group, were
studied computationally and are presented in Figure 3.
Scheme 2. Experiments To Test for Radical Intermediates
The cycloaddition with the Orahovats N-acylurea compound
shows a greater preference for the stepwise biradical pathway
than the Himbert amide case, with TSDi_29−30 located 1.5
kcal/mol lower than the concerted transition structure TS_29−
31. Both pathways lead to the energetically favored cycloadduct
31, with the radical pathway traversing through the diradical
intermediate 30. As expected, the phenyl group on the allene
stabilizes the forming diradical; the intermediate is 16.2 kcal/
mol higher than the starting material, compared with 20.4 kcal/
mol for intermediate 14. Radical recombination is still the rate-
determining step at 24.3 kcal/mol. In short, the computed
energetics for this reaction nicely explain the loss of
enantioenrichment reported by Orahovats as shown in eq 2,
and in close analogy to our observations with amide 18.
The overall lowering of the energetics for the Orahovats
imide may be attributed in part to the destabilization of reactant
29; the methyl substituent on the allene prevents adoption of a
conformation in which the p-orbitals of the allene are
conjugated to the π-system of the amide, thereby preventing
stabilization through conjugative effects. The hydrogen bonding
arrangement (shown in eq 2 and Figure 3) likely also
contributes to the facility of this reaction by biasing in favor
of conformations conducive to cycloaddition.17 As shown
earlier, formation of the formal [2 + 2] cycloadduct is highly
thermodynamically unfavorable and was not modeled in this
reaction.
was readily achieved using Wittig chemistry analogous to the
method previously described by Himbert.15,16 When cyclo-
propyl allene 21 was warmed to 140 °C for 8 h, a relatively
clean mixture of unreacted allene and cycloadduct 23 was
observed; however, at 170 °C, complete decomposition was
observed. This result is consistent with the accessibility of the
cycloreversion reaction, which might permit decomposition via
radical intermediates related to 14. In this case, cyclo-
propylcarbinyl radical ring-opening could lead to a host of
differentand difficult to predictreaction products. In search
of a more compelling outcome, we examined thioether 22. We
Our computational studies strongly suggest that the most
favorable cycloaddition mechanism is a concerted pathway,
because the second steps of the stepwise diradical mechanisms
are highest in energy in both the Himbert and Orahovats
systems. Previously described experimental results from
Orahovats and new results from our group do corroborate
the conclusion reached by computation that the first step of the
stepwise diradical mechanism can be competitive with the
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Figure 3. Calculated energies for the stepwise and direct cycloaddition of arene/allene 29, with transition structure geometries shown below. All
energies shown are in kcal/mol from M06-2X/6-311+G(d,p)/CPCM(THF) single-point calculations on geometries optimized with B3LYP/6-
31G(d). (B3LYP energies are shown in parentheses.)
concerted cycloaddition in both systems; this phenomenon
manifests itself in experiment by incomplete conservation of
enantiopurity. The preference of one pathway over the other
may be influenced by substituents on the benzene or allene
components; substituents that stabilize the forming diradical
should increase the likelihood of the diradical pathway. The fact
that, at lower temperatures, we retained most of the
enantioenrichment with substrate 18 (which bears only a
methyl group in the γ-position of the allene) but the Orahovats
example with the γ-phenyl group suffered greater degradation
of enantioenrichment strongly supports this idea. Most
importantly, a mechanism for racemization of chiral,
enantioenriched allenes is presented by the relatively low
barrier to spirocyclization via a radical manifold, and this
potential issue needs to be considered in planning for the use of
these types of cycloadditions to access enantioenriched
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materials. Fortunately, it appears that computation can provide
guidance in this regard.
Table 1. Computed Thermodynamic Energies (M06-2X, in
kcal/mol) of the Himbert Cycloadditions of Various
Substituted Carbon-Linked Arene/Allenes
Expansion of Substrate Scope to Carbocyclic Sys-
tems. In all of the experiments described by the Himbert and
Orahovats groups, either carboxylic acid derivatives (amides,
esters, thioesters, imides) or phosphorus-based groups
(phosphonate esters, phosphinate esters, phosphinic amides)
were used as tethers.18 No examples of benzyl allenyl ketones
were ever reported; therefore, as a first extension to different
polycyclic architectures, we sought to extend the two-step
sequence to carbon-linked systems. The allenyl ketone
substrates were, for the most part, made by propargyl-metal
additions to arylacetaldehydes followed by oxidation.16,19
Our efforts to extend Himbert cycloaddition reactivity to
these carbon-linked systems were initially met with mixed
results (Scheme 3). Benzyl allenyl ketone 32a was partially
Scheme 3. Representative Himbert Cycloadditions with All-
Carbon Tethers
group at the allene α-position would lead to a favorable reaction
outcome. Most exciting was the observation that donor
(methoxy) and acceptor (carbomethoxy, carboxamide) groups,
alkyl groups (methyl), and a potentially removable substituent
(chloride) all led to thermodynamically favored reactions
according to computation; the fact that such different groups all
led to predicted improvement in reaction outcome strongly
suggests that the origin of the effect is steric in nature. Of the
substrates evaluated by computation, the only outlier to this α-
substituent effect is trimethylsilyl, which is most unusual. On its
own, this result might be explained on the basis of allene
stabilization; however, one would expect the α-methoxy group
to have a significant stabilizing effect on the allene as well.
Attribution to the extreme steric bulk of the group might be
reasonable; however, placing a tert-butyl group at this position,
while overall leading to a thermoneutral reaction, still has a net
benefit on the thermodynamics of the cycloaddition relative to
that of the unsubstituted case. At this stage, we do not have a
clear hypothesis for the trimethylsilyl effect. Because this group
is not beneficial to the cycloaddition chemistry, more detailed
investigations did not seem warranted.
We had posited that placing a donor group on the aromatic
ring to mimic the electronic effects of the nitrogen atom in the
amide-linked cases might lead to equilibria that favored
products. It is evident from the computational data that this
hypothesis was too simplistic; methoxy groups ortho and meta
to the tether lead to favored cycloadditions, whereas placement
in the para position leads to less favorability. Methyl
substitution at the meta position appears detrimental. Clearly,
the thermodynamic profile of these reactions is affected by both
electronic (possible perturbation of either starting material or
converted (∼67%, with slight decomposition) to carbotricycle
33a after heating to 160 °C for 12 h. Longer reaction times did
not improve conversion. Heating isolated cycloadduct 33a to
170 °C established an equilibrium mixture of allene/cyclo-
adduct, clearly demonstrating that the limited conversion of
benzyl allenyl ketone 32a was a thermodynamic issue. On the
other hand, naphthyl system 32b proceeded with complete
conversionlargely to tetracycle 33bunder milder con-
ditions, pointing to both a more kinetically facile and
thermodynamically favorable dearomatization of the fused-
arene system. Starting allene 32b could not be purified to
homogeneity; from material of only about 75% purity, a 54%
yield of cycloadduct was obtained, indicating that the reaction is
relatively efficient (∼70% corrected).
Thermodynamic Considerations and Computational
Guidance. In combination with the calculated exergonicity of
the cycloaddition of amide 13 of only 2 kcal/mol, the
experiments with ketone 32a suggested that many Himbert-
type cycloadditions might be close to thermoneutral. This
problem appears to be particularly prevalent for carbon-linked
systems bearing monocyclic aromatic dienes. Because calcu-
lated energies of reaction for the amide-tethered cases using
M06-2X were quite consistent with experimental results, we
used computation as a predictive tool to see what substitution
patterns on the benzyl allenyl ketone substrates should perturb
the equilibrium toward products (Table 1).
The most important lesson learned from computational
analysis of this reaction type was that substitution of most any
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product ground state energies) and steric factors, and simple
trends corresponding with, for example, Hammett parame-
ters,20 did not become obvious. The beneficial effects appear to
be somewhat additive in some cases, with a highly favored
reaction (5.0 kcal/mol) for the substrate with both allene α-
methyl and arene ο-methyl substituents.
Finally, we note that the presence of a tethered alkene at the
ketone α-position (for prospective metathesis rearrangement)
makes the cycloaddition less favorable, but a benzylic
quaternary center leads to a reaction that is calculated to be
highly favored.
ment afforded by the inclusion of certain substituents on the
allene and the arene offers promise of a relatively general
complexity-generating cycloaddition. Some noteworthy exam-
ples can be found in the next section.
At this stage, we are uncertain why the carbon-linked systems
demonstrate different thermodynamic profiles compared with
heteroatom-linked substrates; there is significant latitude with
respect to linking heteroatoms (nitrogen, oxygen, sulfur)18a,c,d
in the previous reports, suggesting that the detrimental effect of
carbon cannot be readily explained by considerations of
electronegativity or size of the linking atom. However, the
synthetically useful yields obtained in many of the cases in
Table 2 clearly demonstrate that an sp2-hydridized heteroatom
is not absolutely required for successful cycloadditions.
Rapid Generation of Complex Polycycles via Carbon-
Tethered Himbert Cycloaddition and Ring-Rearrange-
ment Metathesis. Because of our desire to access complex,
all-carbon polycyclic scaffolds using this chemistry, we made
several substrates bearing butenyl groups at the benzylic
position. Himbert cycloadditions proceeded similarly to the
unfunctionalized cases shown in Table 2. We are pleased to
report that metathesis rearrangements of the products that we
have generated in this way proceed smoothly to generate the
complex carbopolycycles shown in Table 3. Second-generation
Hoveyda−Grubbs-type catalyst 3623 performed well in these
reactions, as they had in the lactam cases that we had previously
reported.3 In several cases, the cycloaddition efficiency is low, as
expected on the basis of our computational results. On the
other hand, most of the cases are quite efficient, and we note
the excellent results when two substituents that predict
favorability based on computation are combined (especially
37g and 37h). Finally, the metathesis rearrangement process is
efficient in all cases, leading to tri- and tetracyclic compounds
that bear natural-product-like scaffolds. Product 37l is
particularly noteworthy, because of its vicinal quaternary
stereogenic centers.24
Table 2 shows the outcome of many laboratory experiments
that corroborate the computational results. We observed that
Table 2. Scope of the Himbert Arene/Allene Cycloaddition
with All-Carbon Tethers
In all cases, the substrates were synthesized in racemic form,
and the cycloadducts are therefore also obtained in racemic
form. It is noteworthy that the cycloaddition reactions of
substrates bearing groups at the ortho position of the aromatic
ring (those leading to 37b−d, 37g−k, and 37m) are highly
diastereoselective, fortuitously providing as the major isomers
those that can more easily undergo the subsequent metathesis
rearrangement (see 38) to afford polycyclic ketones 37.
Multiple side products were formed in the cycloadditions
leading to 37b and 37c, preventing careful analysis of
diastereoselectivity; however, the others were all formed in at
least 9:1 dr. The high selectivity presumably arises from
minimization of A1,3-strain25 in the reactive conformation/
transition structure, as shown in Figure 4.
a
Conversion values are NMR-based estimates of starting material
disappearance, and undesired side products are often observed.
Perhaps not surprisingly, both the cycloaddition and
metathesis rearrangement steps can be carried out in a single
pot; after consumption of allene 34m, addition of the
ruthenium metathesis catalyst and an atmosphere of ethylene
with warming directly provides 37m in an improved yield as
compared with the two-pot process, likely owing to the
elimination of one purification step (eq 4).
computational predictions were accurate in all reactions that
cleanly proceeded to products; unfortunately, some of the
cycloadditions with carbon tethers were more prone to
decomposition than the amide-tethered cases, likely owing to
facile enol formation and electrocyclic ring-closure, among
other possibilities.21,22 Certainly, the most important results are
those that match the success predicted by computation with the
α-methyl and α-chloro groups on the allene (33f and 33g,
respectively), simply because they indicate that either an alkyl
group or a potentially removable/replaceable chloride will favor
the formation of cycloadducts.
CONCLUSIONS AND FUTURE DIRECTIONS
■
Through the combination of experiment and computation, we
have learned that the dearomatizing arene/allene cycloaddition
first reported by Himbert very likely proceeds by a concerted
process rather than the stepwise radical process put forth by
Although more detailed studies are required, if we assume
additivity in the effects of substituents, the dramatic improve-
H
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Journal of the American Chemical Society
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Table 3. Sequential Himbert Arene/Allene Cycloaddition and Ring-Rearrangement Metathesis to Access All-Carbon Polycycles
a
While the metathesis reaction was very efficient as found on the basis of the NMR spectra of the crude reaction mixture, this product decomposed
b
c
d
upon attempted purification. 17% of the allene starting material was recovered. X-ray structure obtained. The allene starting material was unstable
and precluded accurate yield determination. 90:10 dr, 33% yield of the ketone derived from enol ether hydrolysis was also isolated. 94:6 dr.
e
f
mechanism for the racemization of chiral allenes. We have also
determined that the carbon-tethered Himbert cycloaddition,
which had not been reported previously, is feasible in many
cases, but can suffer from thermodynamic unfavorability with
some substrates. Furthermore, computation provides an
excellent predictive tool for these reactions, which will permit
the evaluation of specific cycloadditions prior to experiment.
Looking forward, we aim to further improve the scope and
efficiency of the carbon-tethered variant, perhaps via catalysis.
We will continue to use computation to evaluate new Himbert-
type systems for feasibility, as we extend to other tether types,
including temporary connections of arene diene and allene
dienophile. Other, nonmetathesis rearrangements of the
strained cycloadducts and applications in complex molecule
synthesis are also under intense study in our laboratories.
Figure 4. Plausible model for diastereocontrol based on minimization
of allylic strain.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental protocols, characterization data, and NMR
spectra for new compounds; complete listing of references
from the Himbert group and all computational data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
houk@chem.ucla.edu; cdv@uci.edu
■
Orahovats. However, the first step of the two-step reaction
proposed by Orahovats can be competitive and offers a
I
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Journal of the American Chemical Society
Article
L.; Celebi-Olcum, N.; Houk, K. N. Angew. Chem., Int. Ed. 2008, 47,
7592−7601.
Author Contributions
†Y.S., J.K.L., and H.V.P contributed equally to this work.
(15) Himbert, G.; Diehl, K.; Schlindwein, H. J. Chem. Ber. 1989, 122,
1691−1699.
Notes
(16) Please see Supporting Information for details.
(17) Himbert, G.; Diehl, K.; Maas, G. J. Chem. Soc., Chem. Commun.
1984, 900−901.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(18) (a) Himbert, G.; Fink, D. Tetrahedron Lett. 1985, 26, 4363−
4366. (b) Trifonov, L. S.; Simova, S. D.; Orahovats, A. S. Tetrahedron
Lett. 1987, 28, 3391−3392. (c) Himbert, G.; Fink, D. Z. Naturforsch.
B; Chem. Sci. 1994, 49, 542−550. (d) Himbert, G.; Ruppmich, M.;
We thank the NSERC of Canada for a graduate fellowship to
J.K.L. and the Humboldt Foundation for a Feodor Lynen
postdoctoral fellowship to Y.S. This work was partially
supported by an NSF CAREER Award (CHE-0847061) and
University of California-Irvine. C.D.V. is grateful for additional
funding from an AstraZeneca Excellence in Chemistry Award,
an Eli Lilly Grantee Award, and an A.P. Sloan Foundation
Fellowship. We thank Materia for a generous donation of
metathesis catalysts. K.N.H. thanks the National Institute of
General Medical Sciences, National Institute of Health GM-
36770. H.V.P. is funded by the UCLA Graduate Division and is
a recipient of the NIH Chemistry-Biology Interface Research
Training Grant (USPHS National Research Service Award
GM-008469).
Knoringer, H. J. Chin. Chem. Soc. 2003, 50, 143−151.
̈
(19) (a) Alcaide, B.; Almendros, P.; Martínez del Campo, T. Eur. J.
Org. Chem. 2007, 2844−2849. (b) Marx, V.; Burnell, D. J. Org. Lett.
2009, 11, 1229−1231.
(20) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science Books: Sausalito, CA, 2006; pp 445−
453.
(21) (a) For an early example of the electrocyclization of a stable
enol derivative, see: Woodward, R. B. Aromaticity; Chemical Society
Special Publication: London, 1967; Vol. 21, p 217. See also:
(b) Shibuya, M. Tetrahedron Lett. 1983, 24, 1175−1178. (c) Buchi, G.;
̈
Leung, J. C. J. Org. Chem. 1986, 51, 4813−4818.
(22) In the amide-tethered variants studied extensively by Himbert,
quinolone formation attributed to electrocyclization was observed in
some cases. For an example, see: Diehl, K.; Himbert, G.; Henn, L.
Chem. Ber. 1986, 119, 2430−2443.
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