Overcoming Kinetic and Thermodynamic Challenges of Classic Cope Rearrangements

Article abstract of DOI:10.1021/acs.joc.0c02690

Systematic evaluation of 1,5-dienes bearing 3,3-electron-withdrawing groups and 4-methylation results in the discovery of a Cope rearrangement for Meldrum's acid-containing substrates that have unexpectedly favorable kinetic and thermodynamic profiles. The protocol is quite general due to a concise and convergent synthesis from abundant starting materials. Furthermore, products with an embedded Meldrum's acid moiety are prepared, which, in turn, can yield complex amides under neutral conditions. We have now expanded the scope of the reductive Cope rearrangement, which, via chemoselective reduction, can promote thermodynamically unfavorable [3,3] sigmatropic rearrangements of 3,3-dicyano-1,5-dienes to form reduced Cope rearrangement products. The Cope rearrangement is found to be stereospecific and can yield enantioenriched building blocks when chiral, nonracemic 1,3-disubstituted allylic electrophiles are utilized. We expand further the use of Cope rearrangements for the synthesis of highly valuable building blocks for complex- and drug-like molecular synthesis.

Full text of DOI:10.1021/acs.joc.0c02690

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Article
Overcoming Kinetic and Thermodynamic Challenges of Classic Cope
Rearrangements
Ehsan Fereyduni,§ Ouidad Lahtigui,§ Jacob N. Sanders,# Breanna M. Tomiczek,# Michael D. Mannchen,
Roland A. Yu, K. N. Houk,* and Alexander J. Grenning*
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ABSTRACT: Systematic evaluation of 1,5-dienes bearing 3,3-
electron-withdrawing groups and 4-methylation results in the
discovery of a Cope rearrangement for Meldrum’s acid-containing
substrates that have unexpectedly favorable kinetic and thermody-
namic profiles. The protocol is quite general due to a concise and
convergent synthesis from abundant starting materials. Further-
more, products with an embedded Meldrum’s acid moiety are
prepared, which, in turn, can yield complex amides under neutral
conditions. We have now expanded the scope of the reductive
Cope rearrangement, which, via chemoselective reduction, can
promote thermodynamically unfavorable [3,3] sigmatropic rear-
rangements of 3,3-dicyano-1,5-dienes to form reduced Cope rearrangement products. The Cope rearrangement is found to be
stereospecific and can yield enantioenriched building blocks when chiral, nonracemic 1,3-disubstituted allylic electrophiles are
utilized. We expand further the use of Cope rearrangements for the synthesis of highly valuable building blocks for complex- and
drug-like molecular synthesis.
Scheme 1. (A, B) Challenges Associated with Nitrile- and
Meldrum’s Acid-Containing 1,5-Dienes and (C)
Malononitrile and Meldrum’s Acid Have a Complementary
Value as Functional Groups
INTRODUCTION
■
The original Cope rearrangement substrates often contained
3,3-dicyano-1,5-diene core structures.1,2 They thermally react
commonly at temperatures >150 °C to yield γ-allyl
alkylidenemalononitriles. In addition to the high kinetic
barrier, these reactions are often thermodynamically unfavor-
able (Scheme 1A). For example, while the 6-unsubstituted
substrate (1a) undergoes clean transformation to the desired
product (2a) at 150 °C, the substituted variants (1b and 1c)
do not.3 Nevertheless, the transformation is often successful
and yields 1,5-dienes bearing a malonic acid variant.4−11 We
hypothesize that 1,5-dienes bearing a Meldrum’s acid moiety at
the 3-position could have improved synthetic utility consider-
ing the versatility of Meldrum’s acid.12−16 For example,
malononitrile can be converted to esters and amides by
oxidative decyanation,17−19 but Meldrum’s acid undergoes
functional group interconversion to esters or amides by simple
thermal treatment in the presence of a heteroatomic
nucleophile (Scheme 1C). Such Meldrum’s acid-containing
1,5-dienes have yet to be reported, likely due to the following
additional challenge: Meldrum’s acid derivatives undergo
retro-[2 + 2 + 2] cycloaddition at temperatures >90 °C,
yielding a ketene, CO2, and acetone (Scheme 1C). This sets up
a chemoselectivity issue for competing thermal transformations
resulting in a limit as to how high Meldrum’s acid-containing
1,5-dienes can be heated (Scheme 1B). While conversion was
observed to some extent for 3a → 4a at 80 °C, the substrate
Received: November 10, 2020
Published: January 21, 2021
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completely decomposed at elevated temperatures (150 °C).
Additionally, the more sterically congested 6-substituted 1,5-
dienes 3b−3c that would yield more complex, vicinal
stereogenic products 4b−4c, respectively, did not react at all
at the lower temperature.
Scheme 3. (A, B) Initial Observation on the Synergistic
Influence of 3-Meldrum’s Acid and 4-Methylation on Cope
Rearrangement Favorability and (C) Why Are 3,3-
Meldrum’s Acid−4-Methyl-1,5-dienes So Reactive?
The kinetic and thermodynamic challenges associated with
3,3-Meldrum’s acid-containing 1,5-dienes, if overcome, would
allow for sequenced thermal transformations (Scheme 2): if a
Scheme 2. Summary of This Work: Reordering of
Preference for Thermal Reactivity Results in a Simple Route
to Complex Amides
class of 1,5-diene substrates could be identified that proceeds
with a reversal of preference for sequenced thermal reactivity
([3,3] first, then Meldrum’s acid retro-[2 + 2 + 2]), then a
modular route to complex amides could be achieved, among
other applications. Such a sequence would be of significant
value considering the simplicity of thermal reactions and the
value of amides in drug discovery.20 We now report that the
Pd-catalyzed allylic alkylation21,22 between alkylidene Mel-
drum’s acid pronucleophiles and 1,3-disubstituted allylic
electrophiles23−29 yields 1,5-dienes that are generally reactive
toward Cope rearrangement at temperatures ranging from a
room temperature of −80 °C, well below the temperature at
which Meldrum’s acid derivatives decompose. The result is a
general synthesis of relatively complex chiral amides from
simple Meldrum’s acid derivatives (Scheme 2).
chromatography, only the Cope product 10a was isolated. As
can be seen in the comparison of 7a and 9a, there is a
significant difference in thermodynamic favorability by the
change in the electron-withdrawing group.
The kinetic and thermodynamic favorability is a synergistic
effect between 3,3-Meldrum’s acid and 4-methylation (Scheme
3C). To reiterate, changing from Meldrum’s acid to
malononitrile (Scheme 3) or removing the 4-methyl group
(Scheme 1A,B) results in significantly less reactive substrates.
This surprising rate enhancement is likely the result of several
physical organic factors: (a) an increased conformation bias for
the reactive σ-cis conformer (e.g. Thorpe−Ingold effect30), (b)
a weaker C3−C4 bond due to increased steric bulk at the
vicinal quaternary/tertiary centers, and (c) the greater
electron-withdrawing ability of Meldrum’s acid moiety.31
To gain a better understanding of the reactivity of this class
of 1,5-dienes, we performed density functional theory
computations to obtain the free-energy profiles of the Cope
rearrangement of malononitrile derivative 7a and Meldrum’s
acid derivative 9a (Scheme 4). The computations reveal that
the two Cope rearrangements have nearly identical kinetic
profiles: malononitrile derivative 7a has a Cope rearrangement
barrier of 25.7 kcal/mol, while Meldrum’s acid derivative 9a
has a Cope rearrangement barrier of 25.0 kcal/mol, and both
transition states have similar partial bond lengths and overall
geometries. These results suggest that the difference in
reactivity between malononitrile derivative 7a and Meldrum’s
acid derivative 9a stems primarily from thermodynamic, rather
than kinetic, factors. Indeed, the Cope rearrangement of
Meldrum’s acid derivative 9a is thermodynamically favorable
(ΔG = −4.7 kcal/mol), primarily owing to the enthalpically
favorable development of additional conjugation with Mel-
drum’s acid moiety (ΔH = −5.1 kcal/mol). The Cope
RESULTS AND DISCUSSION
■
We previously reported that 1,5-dienes derived from
alkylidenemalononitrile and 1,3-diarylallyl electrophiles (chal-
cone derivatives) undergo room-temperature Cope rearrange-
ment.9 We also recently reported that thermodynamically
unfavorable Cope rearrangements can be driven forward by
chemoselective in situ reduction.8,10 We have now examined
the significance of the 3,3-electron-withdrawing group and 4-
methylation on the favorability of allylic transposition. This
study was based on the following initial observations (Scheme
3): 1,5-diene 7a (derived from the alkylidenemalononitrile 5a
and 3-chlorophenyl-1-methylallylcarbonate 6a via Pd-catalyzed
regioselective deconjugative allylation) was poorly reactive to
Cope rearrangement at 150 °C in toluene (∼20% conv. at
equilibrium; decreasing diastereomeric ratio with time). The
analogous Meldrum’s acid scaffold 9a (derived from 8a and
6a) converted to the Cope product 10a transiently at room
temperature with complete conversion, high diastereoselectiv-
ity, and good isolated yield. In the course of the Pd-catalyzed
regioselective deconjugative allylation, 1,5-diene 9a was
observed in crude NMRs, but following workup and
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starting materials are easily available and the synthetic
sequence is straightforward and brief, it is easy to achieve
modular amide synthesis, often with limited purifications in the
sequence. For example, 12a−12h were prepared from
alkylidene Meldrum’s acids 8a−8d and a series of diverse
allylic electrophiles obtained from readily available building
blocks. By modulation of the starting allylic electrophile (6a−
6d), a variety of arenes including 4-chlorophenyl (12a), phenyl
(12b), pentafluorophenyl (12c), and 4-pyridyl (12d) were
incorporated into the products. Using crotonaldehyde
cyanohydrin (6e), a nitrile functional group was installed on
the scaffold yielding 12e. Finally, it was also found that 1,3-
dialkylallyl electrophiles (6f−6g) react regioselectively to
ultimately yield amides bearing 4-N-Boc-piperidyl (12f−12g)
and cyclohexyl (12h) groups at the vicinal stereocenters. With
respect to the scope of the alkylidene Meldrum’s acid 8,
products derived from isovaleraldehyde (12a−12h), N-Boc-
piperidine carboxaldehyde (12i), hydrocinnamaldehyde (12j),
and cis-4-heptenal (12k) were prepared in a range of yields.
Notably, this protocol was optimized for the isovaleraldehyde
substrate (8a). Furthermore, 8a could easily be prepared in
large quantities and was bench-stable. In general, other
Knoevenagel adducts 8b−8d were less stable, which potentially
accounts for the decreased yields through the coupling/Cope
rearrangement sequence. That said, we optimized the synthesis
of 8d, and when used fresh in toluene, we noticed a dramatic
improvement in yield (standard conditions with “older”
samples of 8d resulted in modest yields of product (ca.
19%)). Thus, in many cases, it is prudent to use the alkylidene
Meldrum’s acid derivatives directly after their preparation and/
or take extra precaution in their storage. On this line, examples
12k−12n show a scope study of 8d with a variety of allylic
electrophiles (6a, 6c, 6e, and 6f). The final series of products
12o−12t in Scheme 5 were prepared from 8a, 6a, and a series
of nucleophiles (11a−11g) that react thermally with Mel-
drum’s acid moiety.
Attempts at coupling the ortho-chlorophenylallyl electrophile
6h with the isovaleraldehyde−Meldrum’s acid adduct 8a
resulted in isomeric mixtures of products (Scheme 6).
However, the 2,6-dichlorophenylallyl electrophiles 6i and 8a
were highly competent coupling partners yielding 13a,
exhibiting the opposite regioselectivity of that observed in
Scheme 5. The result might suggest a different reaction
manifold that does not involve Cope rearrangement: we
propose that a direct regioselective γ-allylation is likely
operative as steric shielding would be minimized. Similar to
the previous examples in Scheme 5, 13a was converted to
amide 13b by alkylidene Meldrum’s acid reduction and
thermal amidation.
The unique combination of 3,3-Meldrum’s acid and 4-
methylation onto 1,5-diene architectures allows for kinetic and
thermodynamically favorable Cope rearrangements to occur.
As alluded to in this work, the analogous 3,3-dicyano variants
are not nearly as reactive for both kinetic (150 °C activation
temperature) and thermodynamic (1,5-diene mixtures ob-
served at equilibrium) reasons. For example, a series of 3,3-
dicyano-1,5-dienes with different 6-substituents when heated at
150 °C resulted in varied thermodynamic favorability (Scheme
7). For example, the 6-chlorophenyl substrate (7a) was
unreactive to Cope rearrangement. Interestingly, 6-cyano-
(7b) and 6-ester (7c)-containing substrates underwent Cope
rearrangement with high conversion. Finally, a 6-aliphatic
Scheme 4. Computational Analysis of the Cope
Rearrangement of Meldrum’s Acid- and Malononitrile-
Containing 1,5-Dienes
rearrangement of malononitrile derivative 7a involves instead
the development of additional conjugation with the malononi-
trile moiety, which is also enthalpically favorable, but according
to the computations, by a smaller amount (ΔH = −1.5 kcal/
mol). Moreover, the computed energy difference (ΔG = −1.3
kcal/mol) reflects only the free-energy difference between
single conformations of the starting material and the product.
However, we find that there are relatively few low-lying
product 1,5-diene conformations (6 conformations within 1.4
kcal/mol of the global minimum) compared to starting
material 1,5-diene conformations (36 conformations within
1.4 kcal/mol of the global minimum), meaning that the
ensemble of starting material conformers has higher conforma-
tional entropy than the ensemble of product conformers. This
suggests that the Cope rearrangement of malononitrile
derivative 7a is entropically disfavored, primarily owing to
conformational entropy differences, resulting in the observed
overall thermoneutral ΔG.
Having established an understanding for the deconjugative
alkylation/Cope rearrangement sequence, we set out to
demonstrate that complex amides can be prepared in a simple
convergent fashion via a protocol where thermal Cope
rearrangement and then thermal Meldrum’s acid functional
group interconversion play a key role. Specifically, from
Meldrum’s acid-derived Knoevenagel adducts 8a−8d, allylic
electrophiles 6a−6g, NaBH4, and an amine (or ethanol, 11a−
11g) (Scheme 5), highly complex amides 12a−12s (and an
ester, 12t) were prepared concisely: three steps if the Cope
rearrangement occurred transiently and four if not. Because the
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Scheme 5. Complex Amide Synthesis by Sequenced Thermal Transformations
substrate (7d) was poorly reactive toward Cope rearrangement
conditions.
Our next goal was to extend the scope of the Cope
rearrangement to 3,3,-dicyano-4-methyl-1,5-dienes with varia-
ble groups at the 1- and 6-positions. We recently reported that
3,3-dicyano-1,5-dienes with poor thermodynamic favorability
can be promoted to reduced Cope products via chemoselective
reduction of the in situ generated alkylidenemalononitrile with
Hantzsch amide.8,10 As shown in Scheme 8, this strategy was
generally effective for this previously unreported class of 1,5-
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Scheme 6. Change in Regioselectivity with a 2,6-
Dichlorophenyl Electrophile 6i
Scheme 8. 6-“Functional Group”-4-methyl-3,3-dicyano-1,5-
dienes Undergo Reductive Cope Rearrangement and
Oxidative Decyanation to Yield Complex Esters
Scheme 7. 6-“Functional Group”-4-methyl-3,3-dicyano-1,5-
dienes Are Poor Thermal Cope Rearrangement Substrates
diene.10 Of the initial substrates examined for thermal Cope
rearrangement reactivity (7a−7d), 7b−7d underwent clean
reductive Cope rearrangement and could be converted to
complex esters 14b−14d via malononitrile oxidative ester-
ification (MMPP, magnesium monoperoxyphthalate17)
(Scheme 8). While 7b and 7c already have favorable
thermodynamic profiles, we did notice an increase in
diastereoselectivity when performing the reductive Cope
rearrangement. Thus, the reduction step is occurring faster
than epimerization. While 7a was unreactive, a variety of other
styrene-containing substrates (7e−7h) could be transformed
via reductive Cope rearrangement and converted to esters
14e−14h by oxidative decyanation. Finally, additional nitrile
(14i−14j) and N-Boc-piperidine (14k−14l)-containing esters
were prepared successfully in good to excellent yields and
diastereoselectivity via the two-step procedure.
Having found that aldehyde-derived 3,3-Meldrum’s acid−4-
methyl-1,5-dienes have exceptional kinetic and thermodynamic
profiles (Scheme 3) and that the analogous 3,3-dicyano-4-
methyl-1,5-dienes can be promoted via the reductive Cope
protocol, the final set of 1,5-dienes to explore for Cope
rearrangement reactivity were ketone derivatives (Scheme 9).
A series of malononitrile- (15a−15b) and Meldrum’s acid
(17a−17b)-containing 1,5-dienes for rearrangement to 16 and
18, respectively, were examined. We were pleased to find that
across the full series, there was high thermodynamic
favorability in that all compounds reached high conversion.
Notably, the malononitrile series (15) required heating to 150
°C, whereas Meldrum’s acid series (17) underwent Cope
rearrangement at lower temperatures (rt −80 °C). This is a
similar trend to that observed in the aldehyde-based studies
above.
We next examined the stereoselectivity of the deconjugative
alkylation and Cope rearrangement steps (Scheme 10). Based
on the literature, enantioenriched 1,3-disubstituted allylic
electrophiles should undergo stereospecific allylic alkylation
via a double inversion mechanism.23−29 Through the closed
nature of the Cope rearrangement transition state, this
stereocenter should be relayed into a Cope rearrangement
product bearing vicinal stereocenters.32 To probe this, we
prepared the nitrile-containing allylic electrophile enantioen-
riched by a well-precedented asymmetric transformation,
whereby almond meal provided the necessary biocatalysts.33,34
Under the standard conditions, it was found that the
stereochemistry from the allylic electrophile could indeed be
transposed through the alkylation and Cope rearrangement
sequence with high conservation of ee for both Meldrum’s acid
and malononitrile-derived Knoevenagel adducts. The stereo-
selectivity for the sequence can be ascribed to a double
inversion mechanism on 6h via [I-a] followed by a
diastereoselective Cope rearrangement via the proposed
Zimmerman−Traxler transition state [I-b] (Scheme 11). The
slight erosion of enantiomeric excess in the process can be
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Scheme 9. Ketone-Derived 3,3-Malononitrile- and
Meldrum’s Acid-Containing 1,5-Dienes Have High
Thermodynamic Favorability
Scheme 11. Stereochemical Rationale: (A) Double
Inversion and (B) Zimmerman−Traxler Model
tuted allylic alcohols. Future studies will involve target- and
drug discovery efforts and the development of other new
chemical methods inspired by these discoveries.
EXPERIMENTAL SECTION
■
General Experimental Details. All reactions were carried out
under an atmosphere of nitrogen unless otherwise specified. Reactions
that require heating were done so on stir-heat plates using aluminum
heating blocks (Pie-Blocks; ChemGlass Life Science). Anhydrous
solvents were transferred via a syringe to flame-dried glassware, which
had been cooled under a stream of dry nitrogen. Anhydrous
tetrahydrofuran, pentane, ether, dichloromethane, and toluene were
dried using a commercial solvent purification system. Anhydrous
acetonitrile was dried over CaH2 and obtained via distillation.
Reaction progress was monitored by thin-layer chromatography using
Analtech TLC Uniplate precoated plates and visualized by UV light,
phosphomolybdic acid stain, dinitrophenylhydrazine stain, or KMnO4
stain. Flash column chromatography was performed traditionally or by
a Combiflash Rf+ automated flash chromatography system using a
230−400 mesh 60 Å silica gel. The eluents employed are reported as
volume:volume percentages. Proton-1 nuclear magnetic resonance
(1H NMR) spectra were recorded by a 300, 400, 500, or 600 MHz
spectrometer as indicated. Chemical shifts (δ) are reported in parts
per million (ppm) downfield relative to the solvent residual peak.
Coupling constants (J) are reported in Hz. Multiplicities are reported
using the following abbreviations: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad; and app, apparent. Carbon-13 nuclear
magnetic resonance (13C NMR) spectra were recorded at 75, 100,
125, or 150 MHz with complete proton decoupling. Chemical shifts
are reported in ppm relative to the carbon resonance of the solvent as
indicated. Accurate mass spectra (HRMS) were obtained by the Mass
Spectrometry Research and Education Center at the University of
Florida and are reported as m/z (mass/charge relative ratio) with the
technique indicated using an Agilent Time of Flight 6200
spectrometer. Accurate masses are reported for the molecular ion
(M+) or a suitable fragment ion.
Scheme 10. Enantiospecific Allylic Alkylation/[3,3]
Rearrangement
rationalized by a nucleophilic displacement by Pd(0) on the
Pd-π-allyl intermediate.35
CONCLUSIONS
■
Starting Material Synthesis. Knoevenagel adducts (alkylidene-
malononitriles36 and alkylidene Meldrum’s acid adducts 8a,37 8b−
8d38) were prepared by known procedures. 1,5-Dienes 1a−1c and
3a−3c were prepared by a standard literature procedure deconjuga-
tive alkylation.36,39 rac-6e was prepared by a one-pot cyanohydrin
formation/carbonate formation.40 Enantiomerically enriched (>99%
ee)-6e was prepared enzymatically by the known literature
procedure.33 1,3-Disubstituted allylic electrophiles 6a−6d and 6f−
6g were prepared by a standard literature procedure involving a Wittig
reaction between an aldehyde and triphenylphosphoranylidene-2-
propanone,41 CeCl3/NaBH4/MeOH ketone reduction, and carbonate
formation with methyl chloroformate or Boc2O.
Through the systematic analysis of 1,5-dienes derived by
deconjugative alkylation between Knoevenagel adducts and
1,3-disubstituted electrophiles, we have uncovered surprisingly
mild Cope rearrangements of 3,3-Meldrum’s acid-containing
1,5-dienes and expanded the scope of our reductive Cope
rearrangement protocol. The synthesis of Meldrum’s acid-
containing products is particularly valuable considering the
ease of functional group interconversions of Meldrum’s acid
moiety. We have reported the preparation of a range of
complex amides and esters by thermal functional group
interconversions under neutral conditions. Building blocks
prepared by this method can be rendered enantioenriched via a
stereospecific sequence from chiral, nonracemic 1,3-disubsti-
Wittig Reaction. To a flame-dried Schlenk flask equipped with a
magnetic stir bar were added appropriate carboxaldehyde (1 equiv)
and triphenylphosphoranylidene-2-propanone (1 equiv) in toluene
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(0.67 M) at 100 °C under N2. The reaction mixture was left to stir
until judged complete by TLC analysis. Once the reaction was
finished, toluene was evaporated from the reaction mixture and the
crude material was purified by silica gel flash column chromatography
(30% EtOAc:hexanes) to afford the desired α,β-unsaturated ketone.
1,2-Reduction of α,β-Unsaturated Ketones. To a round-bottom
flask containing a stir bar was added the α,β-unsaturated ketone (1
equiv) in methanol (0.2 M). The reaction flask was then cooled to 0
°C in an ice bath followed by the addition of CeCl3 (1.2 equiv). While
the reaction mixture was still at 0 °C, NaBH4 (3 equiv) was added in
small portions. The reaction was then left to stir at room temperature
for 1 h. Once the reaction was complete, it was diluted with water,
transferred to a separatory funnel, and extracted three times with
EtOAc. The organic layer was then washed with brine, dried with
anhydrous Na2SO4, and the solvent was evaporated in vacuo to afford
a clear oil. The crude material can be used as is for the next step.
Conversion of Allylic Alcohols to Methyl Carbonates. To a flame-
dried Schlenk flask equipped with a magnetic stir bar was added the
racemic secondary alcohol (1 equiv) dissolved in DCM (0.5 M)
under N2. Pyridine (2 equiv) was added, and the reaction flask was
cooled to 0 °C in an ice bath before adding methyl chloroformate (2
equiv). The reaction mixture was brought back to room temperature
and continued stirring until judged complete by TLC analysis. Once
the reaction was complete, the contents of the flask were transferred
to a separatory funnel and washed three times with H2O. The water
layer was back-extracted with DCM, and then the combined organic
layers were washed with brine, dried with Na2SO4, and then the
solvent was removed in vacuo. The crude material was then purified
by silica gel flash column chromatography (15% EtOAc:hexanes) to
produce the desired electrophile.
Conversion of Allylic Alcohols to tert-Butyl Carbonates. Allylic
tert-butyl carbonate electrophiles were prepared by adding the
racemic secondary alcohol (1 equiv) and 4-(dimethylamino)pyridine
(DMAP, 1 mol %) in THF (0.2 M) to a flame-dried round-bottom
flask equipped with a stir bar and a septum. The reaction flask was
then cooled to 0 °C in an ice bath followed by the addition of di-tert-
butyl dicarbonate (1.1 equiv). Immediately upon the addition of di-
tert-butyl dicarbonate, a needle was placed through the septum to
control the release of CO2(g). The reaction mixture was slightly
heated with a heat gun until effervescence was observed. The reaction
was returned to room temperature and continued stirring until
determined complete by TLC. Once the reaction was complete, THF
was evaporated in vacuo and the crude material was purified by silica
gel flash column chromatography.
General Procedure for the Synthesis of Products 12 and 13.
Pd-Catalyzed 1,5-Dienes Synthesis via Regioselective Deconjuga-
tive Allylic Alkylation. Note: the below protocol began on the 0.2−1
mmol scale. A flame-dried Schlenk flask was charged with a stir bar
and Pd(PPh3)4 (5 mol %). CH2Cl2 (0.1 M) was added via a syringe
followed by Knoevenagel adduct (1 equiv), K2CO3 (1.5 equiv), and
subsequently the allylic electrophile (1 equiv). The reaction medium
was stirred at room temperature until completion as determined by
TLC analysis. After reaction, the crude mixture was filtered through a
pad of silica gel and concentrated in vacuo. Purification of the crude
material via column chromatography (hexanes−ethyl acetate)
afforded products, which were directly subjected to Cope rearrange-
ment.
General Procedure for [3,3] Sigmatropic Rearrangement. In
some cases (see Scheme 5), the Cope product was observed during
the purification of the coupling reactions. In other cases, the 1,5-
dienes are charged in a sealed vial and dissolved in toluene (∼0.5 M),
heating at 60−80 °C (specified in Scheme 5) for the indicated period
of time to afford the rearranged products. Toluene was removed in
vacuo, and the crude products were purified by column chromatog-
raphy (hexanes−ethyl acetate) and then directly subjected to NaBH4
reduction.
at 0 °C. After completion, the reaction mixture was quenched by
H2O. The resulting solution was concentrated by rotary evaporation.
The residue was purified via column chromatography (hexanes−ethyl
acetate) and directly subjected to thermal (retro [2 + 2 + 2])
amidation.
General Procedure for Thermal (Retro [2 + 2 + 2]) Amidation.
The reduced Cope product (1 equiv) was charged in a pressure vial
and dissolved in toluene (0.1 M). The amine (or ethanol) (1 equiv)
was added to the vial, and the reaction mixture was heated at 100 °C
until judged complete by TLC. The reaction mixture was transferred
to a separatory funnel. The contents of the separatory funnel were
washed twice with 2 M HCl, and the combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and then
concentrated in vacuo. The crude material was then purified by silica
gel flash column chromatography (EtOAc:hexanes) to afford the final
amide product.
Example Protocol on the 1.36 mmol Scale. A flame-dried 30
mL Schlenk flask was charged with a stir bar and Pd(PPh3)4 (1 mol %,
0.136 mmol, 15 mg). Dry THF (12 mL) was added via a syringe.
Alkylidene Meldrum’s acid 8a (1.36 mmol, 288 mg) was added via a
syringe. The syringe was rinsed with 1 mL of dry THF. Allyl
carbonate 6a (1.1 equiv, 1.50 mmol, 361 mg) was added via a syringe.
The syringe was rinsed with 1 mL of dry THF. The final
concentration was 0.1 M. Cs2CO3 (1.5 equiv, 2.04 mmol, 663 mg)
was added as a powder. The reaction was left to react until completion
as monitored by TLC. After reaction, the crude mixture was filtered
through a pad of silica gel and concentrated in vacuo. Purification of
the crude material via column chromatography (hexanes−ethyl
acetate) directly afforded the Cope rearrangement product 10a
(1.06 mmol, 400 mg, 78% yield).
12a. Isolated: 177 mg (>20:1 dr); yield: 58% over the sequence;
physical state: yellow oil; TLC: Rf = 0.44 (20% EtOAc in hexanes);
purified using 5% EtOAc in hexanes. 1H NMR (400 MHz, CDCl3): δ
7.56 (d, J = 7.9 Hz, 2H), 7.50 (s, 1H), 7.34 (t, J = 7.9 Hz, 2H), 7.27
(d, J = 8.4 Hz, 2H), 7.12 (t, J = 9.0 Hz, 3H), 5.63−5.48 (m, 2H), 3.22
(t, J = 8.6 Hz, 1H), 2.42−2.31 (m, 2H), 1.86 (tdd, J = 9.5, 7.1, 4.3 Hz,
1H), 1.63−1.75 (m, 1H), 1.69 (d, J = 5.3 Hz, 3H), 1.53 (ddd, J =
10.4, 8.4, 4.3 Hz, 2H), 0.90 (d, J = 6.7 Hz, 3H), 0.78 (d, J = 6.7 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3): δ 171.5, 143.7, 138.1,
133.4, 131.5, 129.0, 128.7, 126.3, 124.2, 119.8, 52.8, 48.1, 38.3, 28.8,
23.8, 21.4, 18.1, 16.9. HRMS (ESI) m/z: [M + H]+ calcd for
C23H29ClNO 370.1932; found 370.1911.
12b. Isolated: 30 mg (>20:1 dr); yield: 28% over the sequence;
physical state: yellow oil; TLC: Rf = 0.32 (20% EtOAc in hexanes);
purified using 15% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 7.52 (d, J = 7.9 Hz, 2H), 7.33 (dt, J = 13.4, 7.6 Hz, 4H), 7.21 (t, J =
6.6 Hz, 3H), 7.12 (t, J = 7.3 Hz, 1H), 7.04 (s, 1H), 5.71−5.62 (m,
1H), 5.55 (dq, J = 12.7, 6.3 Hz, 1H), 3.27 (t, J = 9.1 Hz, 1H), 2.40−
2.28 (m, 2H), 1.95−1.83 (m, 1H), 1.70 (d, J = 6.1 Hz, 3H), 1.74−
1.66 (m, 1H), 1.63−1.52 (m, 2H), 0.92 (d, J = 6.9 Hz, 3H), 0.81 (d, J
= 6.7 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 171.4, 145.2,
138.0, 133.8, 129.0, 128.6, 127.6, 126.0, 125.8, 124.1, 119.7, 53.4,
48.2, 38.5, 28.9, 24.0, 21.5, 21.4, 18.1, 17.0. HRMS (ESI) m/z: [M +
Na]+ calcd for C23H29NONa 358.2141; found 358.2162.
12c. Isolated: 62 mg (>20:1 dr); yield: 35% over the sequence %;
physical state: yellow oil; TLC: Rf = 0.55 (20% EtOAc in hexanes);
purified using 10% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 7.51 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 7.7 Hz, 2H), 7.17−7.01 (m,
2H), 5.66 (q, J = 6.7, 5.8 Hz, 2H), 3.73−3.48 (m, 1H), 2.49 (ddd, J =
15.2, 10.1, 5.4 Hz, 1H), 2.36 (ddd, J = 15.1, 10.3, 5.9 Hz, 1H), 1.88
(ddt, J = 12.5, 10.2, 6.4 Hz, 2H), 1.68 (d, J = 5.1 Hz, 3H), 1.64 (ddd,
J = 17.1, 10.3, 6.0 Hz, 2H), 1.43 (pd, J = 6.9, 2.3 Hz, 1H), 0.92 (d, J =
6.9 Hz, 3H), 0.75 (d, J = 6.9 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3): δ 171.0, 138.0, 130.2, 129.2, 129.1, 124.4, 119.8, 45.4, 44.6,
38.3, 29.9, 29.7, 24.1, 21.6, 18.0, 15.9. HRMS (ESI−TOF) m/z: [M +
H]+ calcd for C23H25NOF5 426.1851; found 426.1871.
General Procedure for Alkylidene Reduction. NaBH4 (3 equiv)
was charged in a flame-dried Schlenk flask under N2 and dissolved in
MeOH/THF (1:1 ratio, 0.1 M) at 0 °C. Then, compound alkylidene
Meldrum’s acid (1 equiv) was added dropwise to the previous mixture
12d. Isolated: 3.1 mg (>20:1 dr); yield: 14% over the sequence %;
physical state: yellow oil; TLC: Rf = 0.20 (50% EtOAc in hexanes);
purified using 50% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3) δ
(ppm): 8.50 (s, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.32 (t, J = 7.8 Hz,
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2H), 7.15 (d, J = 4.6 Hz, 2H), 7.10 (t, J = 6.6 Hz, 1H), 7.05 (s, 1H),
5.57 (d, J = 5.9 Hz, 2H), 3.26 (t, J = 8.1 Hz, 1H), 2.33 (t, J = 8.0 Hz,
2H), 1.90−1.80 (m, 1H), 1.69 (d, J = 3.8 Hz, 3H), 1.65−1.60 (m,
1H), 1.53−1.47 (m, 1H), 0.91 (d, J = 6.9 Hz, 3H), 0.88−0.83 (m,
1H), 0.80 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
(ppm): 171.1, 149.7, 132.0, 129.0, 127.5, 124.1, 123.2, 119.7, 52.7,
47.6, 38.0, 29.0, 23.7, 21.3, 18.0, 17.1. HRMS (ESI−TOF) m/z: [M +
H]+ calcd for C22H29N2O 337.2274; found 337.2297.
12e. Isolated: 35.6 mg (>20:1 dr); yield: 14% over the sequence
%; physical state: clear oil; TLC: Rf = 0.10 (20% EtOAc in hexanes);
purified using 30% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 7.54 (d, J = 7.9 Hz, 2H), 7.48 (s, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.12
(t, J = 7.4 Hz, 1H), 6.00−5.81 (m, 1H), 5.37 (ddd, J = 15.2, 6.4, 2.1
Hz, 1H), 3.48−3.36 (m, 1H), 2.59−2.31 (m, 2H), 2.06−1.80 (m,
2H), 1.80−1.71 (m, 4H), 1.66−1.51 (m, 1H), 1.06−0.94 (m, 6H).
13C{1H} NMR (151 MHz, CDCl3): δ 170.6, 138.0, 131.0, 130.1,
129.1, 124.9, 124.4, 124.4, 123.0, 121.0, 119.9, 119.9, 46.2, 46.0, 36.3,
36.2, 35.9, 35.7, 29.6, 24.4, 24.0, 21.4, 19.8, 19.5, 18.5, 17.9, 17.8.
HRMS (ESI−TOF) m/z: [M + H]+ calcd for C18H25N2O 285.1961;
found 285.1948.
12f. Isolated: 62.4 mg (17:1 dr); yield: 24% over the sequence %;
physical state: yellow oil; TLC: Rf = 0.64 (40% EtOAc in hexanes);
purified using 25% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3) δ
(ppm): 7.51 (d, J = 7.9 Hz, 2H), 7.47 (s, 1H), 7.29 (t, J = 7.5 Hz,
2H), 7.07 (t, J = 7.0 Hz, 1H), 5.34 (dt, J = 20.8, 6.0 Hz, 1H), 5.19
(dd, J = 14.5, 10.3 Hz, 1H), 4.05 (bs, J = 36.4 Hz, 2H), 2.61 (dd, J =
30.8, 12.3 Hz, 2H), 2.42−2.23 (m, 2H), 1.86 (dd, J = 12.5, 8.9 Hz,
1H), 1.76−1.68 (m, 2H), 1.65 (d, J = 6.0 Hz, 3H), 1.61−1.52 (m,
2H), 1.44 (s, J = 4.7 Hz, 9H), 1.29−1.22 (m, 1H), 1.14−0.94 (m,
3H), 0.93−0.90 (m, 1H), 0.88 (d, J = 4.8 Hz, 6H).. 13C{1H} NMR
(151 MHz, CDCl3) δ (ppm): 171.52, 154.86, 138.12, 130.99, 128.96,
127.44, 124.08, 119.67, 79.20, 50.05, 43.38, 37.89, 37.28, 30.98, 29.52,
28.48, 24.11, 20.49, 19.47, 18.07. HRMS (ESI−TOF) m/z: [M +
Na]+ calcd for C27H42N2O3Na 465.3088; found 465.3070.
12g. Isolated: 57.8 mg (>20:1 dr); yield: 40% over the sequence;
physical state: pale yellow oil; TLC: Rf = 0.30 (30% EtOAc in
hexanes); purified using 40% EtOAc in hexanes. 1H NMR (600 MHz,
CDCl3) δ (ppm): 5.34 (dd, J = 15.1, 6.4 Hz, 1H), 5.20 (dd, J = 14.5,
10.7 Hz, 1H), 4.08 (bs, J = 19.5, 12.3 Hz, 2H), 3.66 (t, J = 4.6 Hz,
4H), 3.61 (t, J = 3.8 Hz, 2H), 3.43 (t, J = 4.7 Hz, 2H), 2.74−2.52 (m,
2H), 2.35−2.21 (m, 2H), 1.86 (dt, J = 10.2, 6.2 Hz, 1H), 1.79−1.70
(m, 1H), 1.64 (d, J = 6.3 Hz, 3H), 1.61−1.50 (m, 4H), 1.44 (s, 9H),
1.28−1.21 (m, J = 16.1 Hz, 2H), 1.17−0.95 (m, 2H), 0.87 (dd, J =
11.0, 6.8 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ (ppm):
172.0, 154.8, 131.2, 127.3, 79.2, 66.9, 66.7, 50.1, 46.0, 43.6, 41.9, 37.3,
33.6, 28.5, 23.8, 20.5, 18.1. HRMS (ESI−TOF) m/z: [M + Na]+
calcd for C25H44N2O4Na 459.3193; found 459.3187.
12h. Isolated: 12.5 mg (>20:1 dr); yield: 29% over the sequence;
physical state: white solid; TLC: Rf = 0.14 (20% EtOAc in hexanes);
purified using 23% EtOAc in hexanes. 1H NMR (400 MHz, CDCl3) δ
(ppm): 5.36−5.26 (m, 1H), 5.21 (ddd, J = 15.2, 9.7, 1.1 Hz, 1H),
3.66 (dd, J = 6.9, 2.9 Hz, 4H), 3.60 (t, J = 5.2 Hz, 2H), 3.43 (t, J = 4.6
Hz, 2H), 2.33−2.19 (m, 2H), 1.82−1.66 (m, 5H), 1.64 (dd, J = 6.0,
1.1 Hz, 3H), 1.61−1.45 (m, 4H), 1.35−1.04 (m, 6H), 0.97−0.92 (m,
1H), 0.88 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ (ppm): 172.2, 132.1, 126.3, 67.0, 66.7,
51.0, 46.1, 43.8, 41.8, 38.9, 34.1, 32.2, 29.4, 29.1, 27.0−26.6, 24.1,
20.7, 18.6, 18.1. HRMS (ESI−TOF) m/z: [M + Na]+ calcd for
C21H37NO2Na 358.2717; found 358.2743.
12i. Isolated: 14 mg (>20:1 dr); yield: 7% over the sequence;
physical state: yellow oil; TLC: Rf = 0.13 (20% EtOAc in hexanes);
1H NMR (600 MHz, C7D8 at 80 °C): δ 7.41 (d, J = 7.7 Hz, 1H),
7.02−7.00 (m, 8H), 6.89−6.88 (m, 1H), 5.54 (dd, J = 15.1, 9.2 Hz,
1H), 5.34 (dq, J = 12.7, 6.3 Hz, 1H), 4.18 (d, J = 12.1 Hz, 2H), 3.16
(t, J = 8.3 Hz, 1H), 2.37−2.30 (m, 2H), 1.97−1.84 (m, 3H), 1.69 (dd,
J = 13.0, 7.4 Hz, 2H), 1.58 (dd, J = 6.4, 1.3 Hz, 2H), 1.47 (s, 9H),
1.36−1.29 (m, J = 21.4, 10.0 Hz, 6H). 13C{1H} NMR: see gHMBC
data in the Supporting Information. HRMS (ESI) m/z: [M + Na]+
calcd for C30H39N2O3ClNa 533.2515; found 533.2515.
12j. Isolated: 22 mg (>20:1 dr); yield: 14% over the sequence %;
physical state: yellow oil; TLC: Rf = 0.43 (20% EtOAc in hexanes);
purified using 10% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 7.42 (d, J = 7.9 Hz, 2H), 7.34−7.29 (m, 5H), 7.22 (t, J = 7.4 Hz,
2H), 7.14 (t, J = 8.6 Hz, 5H), 6.76 (s, 1H), 5.69 (dd, J = 14.7, 10.0
Hz, 1H), 5.55 (dq, J = 12.9, 6.3 Hz, 1H), 3.27−3.20 (m, 1H), 2.64
(dd, J = 13.9, 6.4 Hz, 1H), 2.46 (dd, J = 13.9, 7.9 Hz, 1H), 2.27 (ddd,
J = 15.4, 9.5, 5.8 Hz, 1H), 2.24−2.18 (m, 1H), 2.11 (dt, J = 14.6, 7.2
Hz, 1H), 1.94−1.87 (m, 1H), 1.75 (dd, J = 6.4, 1.0 Hz, 3H), 1.73−
1.64 (m, 1H). 13C{1H} NMR (151 MHz, CDCl3): δ 170.9, 142.9,
141.0, 137.8, 131.8, 130.9, 129.2, 129.0, 129.0, 128.7, 128.6, 128.5,
128.1, 127.3, 126.1, 124.2, 119.6, 51.4, 44.7, 38.3, 35.3, 29.7, 26.4,
22.7, 18.2, 14.1. HRMS (ESI) m/z: [M + H]+ calcd for C27H28ClNO
418.1932; found 418.1946.
12k. Isolated: 20 mg (>20:1 dr); yield: 17% over the sequence;
physical state: yellow oil. TLC: Rf = 0.33 (20% EtOAc in hexanes);
purified using 10% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 7.50 (d, J = 7.8 Hz, 2H), 7.34 (t, J = 7.9 Hz, 2H), 7.28−7.26 (m,
2H), 7.12 (d, J = 8.2 Hz, 3H), 7.06 (s, 1H), 5.61 (dd, J = 14.7, 9.6 Hz,
1H), 5.51 (dt, J = 21.6, 6.3 Hz, 1H), 5.44 (dd, J = 17.8, 7.3 Hz, 1H),
5.32 (dd, J = 17.5, 7.2 Hz, 1H), 3.21 (t, J = 8.5 Hz, 1H), 2.46−2.39
(m, 1H), 2.30−2.23 (m, 1H), 2.08−2.02 (m, 1H), 1.94−1.91 (m,
3H), 1.87−1.80 (m, 1H), 1.70 (d, J = 5.4 Hz, 3H), 1.14−1.11 (m,
1H), 0.99 (td, J = 7.5, 2.5 Hz, 1H), 0.93 (t, J = 7.5 Hz, 3H). 13C{1H}
NMR (151 MHz, CDCl3): δ 171.1, 143.0, 137.9, 133.5, 131.7, 129.2,
129.0, 128.6, 127.3, 126.2, 124.2, 119.7, 51.8, 42.7, 35.3, 28.5, 26.3,
20.8, 18.1, 14.2. HRMS (ESI) m/z: [M + Na]+ calcd for
C25H30NOClNa 418.1908; found 418.1880.
12l. Isolated: 13.2 mg (>20:1 dr); yield: 17% over the sequence %;
physical state: clear oil. TLC: Rf = 0.33 (10% EtOAc in hexanes);
purified using 10% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 7.50 (d, J = 7.9 Hz, 2H), 7.38−7.28 (m, 2H), 7.21−7.04 (m, 2H),
5.76−5.58 (m, 2H), 5.39 (dt, J = 11.3, 7.4 Hz, 1H), 5.21 (q, J = 7.7
Hz, 1H), 3.55 (t, J = 9.8 Hz, 1H), 2.45 (ddd, J = 15.5, 10.6, 5.4 Hz,
1H), 2.32 (dtd, J = 15.2, 10.4, 9.8, 4.9 Hz, 1H), 2.12−2.06 (m, 1H),
2.05−1.98 (m, 2H), 1.96−1.79 (m, 3H), 1.72 (tq, J = 8.9, 5.7, 3.8 Hz,
1H), 1.67 (dd, J = 5.9, 1.3 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H). 13C{1H}
NMR (151 MHz, CDCl3): δ 170.9, 138.0, 133.9, 129.7, 129.4, 129.2,
125.0, 124.4, 119.8, 44.0, 39.7, 34.8, 29.9, 28.6, 27.0, 20.8, 18.0, 14.2.
HRMS (ESI−TOF) m/z: [M + H]+ calcd for C25H27NOF5 452.2008;
found 452.2008.
12m. Isolated: 32.2 mg (>20:1 dr); yield: 28% over the sequence;
physical state: clear oil; TLC: Rf = 0.30 (25% EtOAc in hexanes);
purified using 30% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 7.50 (d, J = 7.9 Hz, 2H), 7.38−7.28 (m, 2H), 7.21−7.04 (m, 2H),
5.76−5.58 (m, 2H), 5.39 (dt, J = 11.3, 7.4 Hz, 1H), 5.21 (q, J = 7.7
Hz, 1H), 3.55 (t, J = 9.8 Hz, 1H), 2.45 (ddd, J = 15.5, 10.6, 5.4 Hz,
1H), 2.32 (dtd, J = 15.2, 10.4, 9.8, 4.9 Hz, 1H), 2.12−2.06 (m, 1H),
2.05−1.98 (m, 2H), 1.96−1.79 (m, 3H), 1.72 (tq, J = 8.9, 5.7, 3.8 Hz,
1H), 1.67 (dd, J = 5.9, 1.3 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H). 13C{1H}
NMR (126 MHz, CDCl3): δ 170.9, 138.0, 133.9, 129.7, 129.4, 129.2,
125.0, 124.4, 119.8, 44.0, 39.7, 34.8, 29.9, 28.6, 27.0, 20.8, 18.0, 14.2.
HRMS (ESI−TOF) m/z: [M + Na]+ calcd for C20H26N2ONa
333.1943; found 333.1924.
12n. Isolated: 36.6 mg (>20:1 dr); yield: 17% over the sequence;
physical state: brown oil; TLC: Rf = 0.43 (30% EtOAc in hexanes);
purified using 25% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3) δ
(ppm): 7.51 (d, J = 7.9 Hz, 2H), 7.47 (s, 1H), 7.30 (t, J = 7.8 Hz,
2H), 7.08 (t, J = 7.3 Hz, 1H), 5.40 (dd, J = 17.5, 7.3 Hz, 1H), 5.32
(td, J = 12.7, 6.3 Hz, 1H), 5.23 (dd, J = 16.7, 7.6 Hz, 1H), 5.12 (dd, J
= 14.4, 10.6 Hz, 1H), 4.05 (m, 2H), 2.69−2.56 (m, 2H), 2.47 (ddd, J
= 14.8, 10.0, 5.0 Hz, 1H), 2.30−2.19 (m, 1H), 2.07−1.95 (m, 5H),
1.94−1.86 (m, 1H), 1.80−1.70 (m, 2H), 1.66 (d, J = 5.9 Hz, 3H),
1.65−1.53 (m, 4H), 1.43 (s, 9H), 1.03 (ddd, J = 23.9, 12.0, 3.3 Hz,
1H), 0.95 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
(ppm): 171.4, 154.8, 138.1, 132.9, 129.8, 129.0, 128.1, 127.6, 124.1,
119.7, 79.2, 50.6, 37.9, 36.5, 35.9, 30.5, 29.1, 28.5, 25.8, 20.9, 18.0,
14.2. HRMS (ESI−TOF) m/z: [M + Na]+ calcd for C29H44N2O3Na
491.3244; found 491.3206.
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12o. Isolated: 62 mg (>20:1 dr); yield: 50% over the sequence;
physical state: yellow oil; TLC: Rf = 0.28 (50% EtOAc in hexanes);
purified using 50% EtOAc in hexanes. 1H NMR (400 MHz, CDCl3):
δ 7.28−7.25 (m, 2H), 7.13−7.08 (m, 2H), 5.64−5.40 (m, 2H), 3.69−
3.56 (m, 6H), 3.34 (dd, J = 10.7, 6.0 Hz, 2H), 3.21 (t, J = 8.4 Hz,
1H), 2.36−2.19 (m, 2H), 1.73 (ddd, J = 19.1, 11.3, 5.8 Hz, 1H), 1.66
(d, J = 5.1 Hz, 3H), 1.57−1.45 (m, 3H), 0.88 (d, J = 6.7 Hz, 3H),
0.77 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 171.8,
143.7, 133.4, 131.5, 128.9, 128.6, 126.2, 66.9, 66.7, 52.7, 48.4, 46.0,
41.8, 34.3, 28.9, 23.6, 21.4, 18.1, 16.9. HRMS (ESI) m/z: [M + H]+
calcd for C21H30ClNO2 364.2038; found 364.2050.
12p. Isolated: 19 mg (>20:1 dr); yield: 60% over the sequence;
physical state: yellow oil; TLC: Rf = 0.14 (20% EtOAc in hexanes);
purified using 20% EtOAc in hexanes. 1H NMR (400 MHz, CDCl3):
δ 7.40−7.24 (m, 8H), 7.09 (d, J = 8.4 Hz, 2H), 5.58−5.48 (m, 2H),
4.44 (t, J = 5.7 Hz, 2H), 3.19 (t, J = 8.6 Hz, 1H), 2.28−2.19 (m, 2H),
1.83−1.75 (m, 1H), 1.66 (s, 1H), 1.64 (d, J = 5.1 Hz, 3H), 1.56−1.48
(m, 2H), 0.88 (d, J = 6.7 Hz, 3H), 0.76 (d, J = 6.7 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 171.5, 143.7, 138.1, 133.4, 131.5, 129.0,
128.7, 126.3, 124.2, 119.8, 52.8, 48.1, 38.3, 28.8, 23.8, 21.4, 18.1, 16.9.
HRMS (ESI) m/z: [M + Na]+ calcd for C24H30NOClNa 406.1914;
found 406.1894.
12q. Isolated: 48 mg (>20:1 dr); yield: 59% over the sequence;
physical state: yellow oil; TLC: Rf = 0.14 (20% EtOAc in hexanes);
purified using 30% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 7.28−7.24 (m, 4H), 7.09 (dd, J = 8.2, 1.6 Hz, 2H), 7.04 (td, J = 8.5,
1.7 Hz, 2H), 5.65 (s, 1H), 5.58−5.45 (m, 2H), 4.39 (d, J = 5.1 Hz,
2H), 3.19 (t, J = 8.6 Hz, 1H), 2.26−2.15 (m, 2H), 1.82−1.75 (m,
1H), 1.64 (d, J = 5.8 Hz, 3H), 1.62−1.56 (m, 1H), 1.50 (d, J = 5.6
Hz, 2H), 0.87 (d, J = 5.1 Hz, 3H), 0.76 (d, J = 5.0 Hz, 3H). 13C{1H}
NMR (151 MHz, CDCl3): δ 172.8, 163.0, 161.4, 143.6, 134.3, 133.4,
131.5, 129.5 (d, J = 8.1 Hz), 128.9, 128.6, 126.2, 115.6, 115.5, 77.3,
77.1, 76.8, 52.7, 48.1, 42.8, 37.2, 28.8, 23.9, 21.4, 18.0, 16.9. HRMS
(ESI) m/z: [M + H]+ calcd for C24H30ClFNO 402.1999; found
402.1980.
12r. Isolated: 39 mg (>20:1 dr); yield: 39% over the sequence;
physical state: yellow oil; TLC: Rf = 0.38 (20% EtOAc in hexanes);
purified using 10% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 7.64 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7
Hz, 2H), 7.13 (t, J = 10.5 Hz, 3H), 5.64−5.50 (m, 2H), 3.25 (t, J =
8.7 Hz, 1H), 2.43−2.31 (m, 2H), 1.90−1.83 (m, 1H), 1.69 (d, J = 5.3
Hz, 3H), 1.74−1.65 (m, 1H), 1.59−1.51 (m, 2H), 0.91 (d, J = 6.7 Hz,
3H), 0.80 (d, J = 6.7 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ
171.4, 143.5, 141.0, 133.2, 131.6, 128.9, 128.7, 126.5, 126.30 (q, J =
3.8 Hz), 119.2, 52.6, 48.1, 38.4, 28.9, 23.6, 21.4, 18.1, 17.0. HRMS
(ESI) m/z: [M + H]+ calcd for C24H27ClF3NO 438.1806; found
438.1782.
12s. Isolated: 39 mg (>20:1 dr); yield: 48% over the sequence;
physical state: yellow oil. TLC: Rf = 0.68 (20% EtOAc in hexanes);
purified using 5% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3): δ
8.24−8.22 (m, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 7.68 (dd, J = 8.8, 2.2
Hz, 1H), 7.28 (dd, J = 9.0, 4.7 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H),
5.60−5.50 (m, 2H), 3.21 (t, J = 8.4 Hz, 1H), 2.49−2.31 (m, 2H),
1.89−1.81 (m, 1H), 1.68 (d, J = 4.7 Hz, 3H), 1.72−1.63 (m, 1H),
1.58−1.49 (m, 2H), 0.89 (d, J = 6.8 Hz, 3H), 0.78 (d, J = 6.7 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3): δ 171.5, 149.7, 146.4,
143.4, 138.0, 133.4, 131.6, 128.8, 128.7, 126.6, 126.4, 114.6, 52.9,
48.0, 38.4, 28.7, 23.5, 21.4, 18.0, 16.7. HRMS (ESI) m/z: [M + H]+
calcd for C22H27N2OCl2 405.1500; found 405.1477.
12t. Isolated: 28 mg (>20:1 dr); yield: 43% over the sequence;
physical state: yellow oil. TLC: Rf = 0.68 (20% EtOAc in hexanes);
purified using 10% EtOAc in hexanes. 1H NMR (500 MHz, CDCl3):
δ 7.28−7.25 (m, 2H), 7.13−7.09 (m, 2H), 5.58−5.45 (m, 2H), 4.13
(q, J = 7.1 Hz, 2H), 3.16 (t, J = 8.9 Hz, 1H), 2.41−2.25 (m, 2H),
1.80−1.70 (m, 1H), 1.67 (d, J = 5.0 Hz, 3H), 1.61−1.58 (m, 1H),
1.53−1.47 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H),
0.75 (d, J = 6.7 Hz, 3H).; 13C{1H} NMR (126 MHz, CDCl3): δ
173.8, 143.6, 133.5, 128.9, 128.6, 126.0, 64.2, 60.2, 53.0, 47.8, 42.5,
34.9, 28.5, 23.0, 21.4, 17.9, 16.6, 14.3. HRMS (DART) m/z: [M +
H]+ calcd for C19H28ClO2 323.1778; found 323.1757.
13b. Isolated: 113 mg (>20:1 dr); yield: 41% over the sequence;
physical state: yellow oil; TLC: Rf = 0.28 (50% EtOAc in hexanes);
purified using 40% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 7.30 (d, J = 8.1 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.35 (d, J = 16.2
Hz, 1H), 6.18 (dd, J = 16.2, 8.1 Hz, 1H), 3.62 (d, J = 32.3 Hz, 6H),
3.47−3.39 (m, 2H), 2.59−2.52 (m, 1H), 2.43−2.35 (m, 1H), 2.33−
2.27 (m, 1H), 1.93−1.84 (m, 1H), 1.74−1.65 (m, 2H), 1.23−1.19
(m, 1H), 1.17 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 0.94 (d, J
= 6.8 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 171.9, 143.9,
135.2, 134.3, 128.4, 127.7, 122.9, 66.9, 66.6, 49.1, 46.0, 41.8, 39.9,
33.5, 29.2, 23.5, 21.2, 19.0, 19.0. HRMS (ESI) m/z: [M + H]+ calcd
for C21H29Cl2O2N 398.1648; found 398.1684.
General Procedure for the Synthesis of Products 14. Pd-
Catalyzed 1,5-Dienes Synthesis via Regioselective Deconjugative
Allylic Alkylation. Note: the below protocol began on the 0.2−1
mmol scale. A flame-dried Schlenk flask was charged with a stir bar
and Pd(PPh3)4 (5 mol %). CH2Cl2 (0.1 M) was added via a syringe
followed by Knoevenagel adduct (1 equiv), K2CO3 (1.5 equiv), and
subsequently the allylic electrophile (1 equiv). The reaction medium
was stirred at room temperature until completion as determined by
TLC analysis. After reaction, the crude mixture was filtered through a
pad of silica gel and concentrated in vacuo. Purification of the crude
material via column chromatography (hexanes−ethyl acetate)
afforded products, which were directly subjected to reductive Cope
rearrangement.
General Procedure for Reductive Cope Rearrangement. 1,5-
Diene (1 equiv) and Hantzsch amide (3 equiv) were charged in a
pressure vial and diluted in toluene (∼0.5 M) and heated up to 120−
150 °C (specified with substrate) for the indicated period of time to
afford the rearranged products. Toluene was removed in vacuo, and
the crude products were purified by column chromatography
(hexanes−ethyl acetate) and directly subjected to oxidative
esterification.
General Procedure for Oxidative Esterification. The alkyl-
malononitrile prepared via reductive Cope rearrangement was
dissolved in MeOH (0.1 M) and cooled to 0 °C. K2CO3 (1.5
equiv) was then added, followed by MMPP·6H2O (1.5 equiv), and
the reaction was slowly warmed to room temperature and stirred for
30 min to 1 h. The reaction was then diluted with EtOAc and washed
with H2O, brine, and dried over anhydrous Na2SO4. The organic layer
was concentrated under reduced pressure, and the crude material was
then purified via flash column chromatography (hexanes−ethyl
acetate).
14b. Isolated: 20 mg (>20:1 dr); yield: 32% over the sequence;
physical state: clear oil. TLC: Rf = 0.30 (20% EtOAc in hexanes);
purified using 20% EtOAc in hexanes. 1H NMR (400 MHz, CDCl3):
δ 7.52 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 7.9 Hz, 2H), 7.11 (d, J = 8.0
Hz, 1H), 5.85 (dqd, J = 14.7, 6.7, 1.5 Hz, 1H), 5.64−5.44 (m, 1H),
5.38−5.18 (m, 2H), 3.49−3.33 (m, 1H), 2.58−2.29 (m, 2H), 2.29−
2.11 (m, 2H), 2.10−1.93 (m, 2H), 1.92−1.80 (m, 2H), 1.79−1.75
(m, 1H), 1.74−1.71 (m, 4H), 0.97 (tt, J = 7.5, 4.2 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 173.3, 131.5, 123.5, 120.0, 52.0, 42.9,
37.7, 32.5, 28.9, 21.5, 17.8, 17.2. HRMS (ESI−TOF) m/z: [M +
NH4]+ calcd for C12H23N2O2 227.1758; found 227.1756.
14c. Isolated: 36 mg (>20:1 dr); yield: 61% over the sequence;
physical state: yellow oil; TLC: Rf = 0.30 (15% EtOAc in hexanes);
purified using 15% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 5.71−5.49 (m, 1H), 5.36 (ddq, J = 15.1, 9.7, 1.7 Hz, 1H), 4.21−
4.02 (m, 2H), 3.63 (s, 3H), 3.07−2.86 (m, 1H), 2.46−2.31 (m, 1H),
2.27−2.07 (m, 2H), 1.69−1.63 (m, 4H), 1.24 (t, J = 7.1 Hz, 3H),
0.96−0.77 (m, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 174.1,
173.8, 129.9, 127.6, 60.4, 53.7, 51.5, 42.4, 32.5, 29.6, 21.1, 17.9, 16.9,
14.2. HRMS (ESI−TOF) m/z: [M + H]+ calcd for C14H25O4
257.1747; found 257.1750.
14d. Isolated: 19.1 mg (5:1 dr); yield: 39% over the sequence;
physical state: oil; TLC: Rf = 0.45 (20% EtOAc in hexanes); purified
using 13% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ (ppm)
major diastereomer: 5.43 (dq, 1H), 5.19−4.97 (m, 1H), 4.10 (bs, 2H),
3.63 (s, 3H), 2.73−2.47 (m, 2H), 2.15 (d, J = 5.8 Hz, 2H), 2.00−1.92
(m, 1H), 1.87−1.78 (m, 1H), 1.76−1.66 (m, 2H), 1.62 (dd, J = 6.4,
2640
https://dx.doi.org/10.1021/acs.joc.0c02690
J. Org. Chem. 2021, 86, 2632−2643

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1.5 Hz, 3H), 1.44 (s, 9H), 1.30−1.13 (m, 2H), 1.12−0.95 (m, 2H),
0.88 (d, J = 6.7 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ (ppm): 175.0, 154.8, 130.1, 128.2, 79.2, 51.5,
50.2, 40.6, 36.9, 33.4, 28.5, 21.2, 18.0. HRMS (ESI−TOF) m/z: [M +
Na]+ calcd for C21H37NO4Na 390.2615; found 390.2601.
14k. Isolated: 16.6 mg (7:1 dr); yield: 31% over the sequence;
physical state: yellow oil; TLC: Rf = 0.38 (20% EtOAc in hexanes);
purified using 11% EtOAc in hexanes. H NMR (600 MHz, CDCl3)
1
major diastereomer: δ 5.43−5.37 (m, 1H), 5.34 (dq, J = 14.9, 6.4 Hz,
1H), 5.26−5.19 (m, 1H), 5.12−4.97 (m, 1H), 4.08 (bs, J = 9.7 Hz,
2H), 3.64 (s, 3H), 2.62 (bs, 2H), 2.32 (dd, J = 15.2, 4.0 Hz, 1H),
2.18−2.12 (m, 1H), 2.10−1.96 (m, 6H), 1.77 (ddd, J = 9.9, 7.8, 5.4
Hz, 1H), 1.66 (dd, J = 6.4, 1.5 Hz, 3H), 1.62 (s, 1H), 1.55 (dd, J =
6.9, 1.7 Hz, 1H), 1.44 (s, 9H), 1.17−1.07 (m, 1H), 1.06−0.97 (m,
1H), 0.94 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
(ppm): 174.2, 154.8, 133.4, 129.4, 128.7, 126.5, 79.2, 51.5, 50.3, 36.7,
35.6, 35.5, 30.1, 28.5, 20.7, 18.0, 14.2. HRMS (ESI−TOF) m/z: [M +
Na]+ calcd for C23H39NO4Na 416.2771; found 416.2751.
14l. Isolated: 21.4 mg (6.9:1 dr); yield: 43% over the sequence;
physical state: white solid. TLC: Rf = 0.25 (15% EtOAc in hexanes);
purified using 13% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3) δ
(ppm): 7.29−7.12 (m, 5H), 5.37 (dq, J = 12.8, 6.3 Hz, 1H), 5.09 (dd,
J = 15.0, 10.1 Hz, 1H), 4.03 (bs, J = 47.1 Hz, 2H), 3.59 (s, J = 23.1
Hz, 3H), 2.66−2.02 (m, 6H), 1.73−1.65 (m, 4H), 1.60 (d, J = 11.7
Hz, 1H), 1.42 (s, 9H), 1.40−1.32 (m, 1H), 1.25 (s, J = 8.6 Hz, 2H),
1.01−0.84 (m, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ (ppm):
174.0, 154.7, 140.3, 129.2, 128.3, 126.0, 79.2, 51.5, 49.9, 39.1, 36.8,
35.2, 28.5, 18.1. HRMS (ESI−TOF) m/z: [M + Na]+ calcd for
C25H37NO4Na 438.2615; found 438.2602.
14e. Isolated: 22 mg (>20:1 dr); yield: 17% over the sequence;
physical state: yellow oil. TLC: Rf = 0.55 (20% EtOAc in hexanes);
1
purified using 5% EtOAc in hexanes. H NMR (400 MHz, CDCl3)
major diastereomer: δ 7.30−7.27 (m, 2H), 7.17−7.13 (m, 2H), 5.53−
5.49 (m, 2H), 5.46−5.39 (m, 1H), 5.28−5.21 (m, 1H), 3.65 (s, 3H),
3.18−3.13 (m, 1H), 2.39−2.27 (m, 3H), 1.98 (dd, J = 14.8, 6.0 Hz,
1H), 1.94−1.83 (m, 3H), 1.66 (d, J = 4.6 Hz, 3H), 0.91 (t, J = 7.5 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3): δ 178.5, 157.1, 134.0,
132.1, 129.2, 128.6, 127.7, 127.3, 125.6, 52.7, 51.5, 40.0, 36.1, 29.4,
20.6, 18.0, 14.1. HRMS (DART) m/z: [M + H]+ calcd for
C19H26ClO2 321.1616; found 321.1601.
14f. Isolated: 29 mg (>5:1 dr); yield: 23% over the sequence;
physical state: yellow oil TLC: Rf = 0.55 (20% EtOAc in hexanes);
purified using 10% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 5.69−5.48 (m, 2H), 4.00 (t, J = 10.6 Hz, 0H), 3.66 (d, J = 4.9 Hz,
3H), 3.53 (dd, J = 11.3, 9.2 Hz, 1H), 2.73−2.55 (m, 1H), 2.33 (dt, J =
16.2, 4.4 Hz, 1H), 2.16 (dd, J = 16.2, 7.4 Hz, 1H), 1.72−1.59 (m,
3H), 1.55−1.37 (m, 1H), 0.92−0.65 (m, 6H). 13C{1H} NMR (151
MHz, CDCl3): δ 174.2, 129.7, 129.4, 51.7, 44.4, 42.3, 33.2, 29.2, 29.0,
21.6, 21.5, 17.8, 15.6. HRMS (ESI−TOF) m/z: [M + H]+ calcd for
C17H20O2F5 351.1378; found 351.1376.
14g. Isolated: 23 mg (>20:1 dr); yield: 27% over the sequence;
physical state: yellow oil; TLC: Rf = 0.45 (30% EtOAc in hexanes);
purified using 20% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 5.62 (p, J = 3.3, 2.8 Hz, 2H), 5.39 (dtt, J = 10.6, 7.3, 1.7 Hz, 1H),
5.16 (dddd, J = 11.0, 9.1, 5.1, 1.7 Hz, 1H), 3.65 (s, 3H), 3.62−3.53
(m, 1H), 2.66−2.53 (m, 1H), 2.43 (dd, J = 16.1, 5.4 Hz, 1H), 2.39−
2.27 (m, 1H), 2.05−1.78 (m, 4H), 1.69−1.60 (m, 3H), 0.95−0.80
(m, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 173.3, 134.5, 130.1,
129.0, 124.8, 51.6, 44.2, 37.6, 36.6, 29.8, 20.6, 17.9, 14.1. HRMS
(ESI−TOF) m/z: [M + H]+ calcd for C19H22O2F5 377.1534; found
377.1521.
14h. Isolated: 34.4 mg (>20:1 dr); yield: 72% over the sequence;
physical state: clear oil. TLC: Rf = 0.70 (20% EtOAc in hexanes);
purified using 10% EtOAc in hexanes. 1H NMR (400 MHz, CDCl3):
δ 7.20 (t, J = 5.9 Hz, 2H), 7.13 (t, J = 6.3 Hz, 1H), 7.02 (d, J = 8.9 Hz,
2H), 5.84−5.43 (m, 2H), 3.73−3.62 (m, 1H), 3.58 (s, 3H), 2.96−
2.69 (m, 1H), 2.61−2.45 (m, 2H), 2.43−2.22 (m, 2H), 1.65 (d, J =
4.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 173.0, 139.3,
130.2, 128.9, 128.4, 126.3, 77.4, 51.6, 44.8, 39.3, 36.9, 31.7, 22.8, 17.9,
14.3. HRMS (ESI−TOF) m/z: [M + H]+ calcd for C21H20O2F5
399.1378; found 399.1378.
14i. Isolated: 29 mg (>20:1 dr); yield: 40% over the sequence;
physical state: orange oil; TLC: Rf = 0.45 (30% EtOAc in hexanes);
purified using 25% EtOAc in hexanes. 1H NMR (600 MHz, CDCl3):
δ 5.86 (dqd, J = 14.7, 6.7, 1.6 Hz, 1H), 5.58−5.47 (m, 1H), 5.42−
5.21 (m, 2H), 3.68−3.46 (s, 3H), 3.55−3.46 (m, 1H), 2.51−2.29 (m,
2H), 2.27−2.12 (m, 3H), 2.10−1.99 (m, 2H), 1.79−1.68 (m, 3H),
1.01−0.92 (m, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 172.7,
135.8, 135.3, 131.5, 131.2, 124.8, 124.8, 123.2, 123.0, 119.3, 118.9,
51.9, 38.3, 38.2, 37.9, 37.4, 35.6, 35.1, 30.2, 28.2, 20.8, 17.9, 17.8,
14.3, 14.2. HRMS (ESI−TOF) m/z: [M + Na]+ calcd for
C14H21NO2Na 258.1470; found 258.1464.
14j. Isolated: 17.2 mg (>20:1 dr); yield: 51% over the sequence;
physical state: yellow oil; TLC: Rf = 0.45 (15% EtOAc in hexanes);
purified using 10% EtOAc in hexanes. 1H NMR (400 MHz, CDCl3):
δ 7.30 (tt, J = 6.7, 1.1 Hz, 2H), 7.25−7.13 (m, 3H), 5.89−5.39 (ddq, J
= 15.2, 6.3, 1.7 Hz, 3H), 5.21 (ddq, J = 15.3, 5.3, 1.7 Hz, 0H), 3.64 (d,
J = 15.1 Hz, 3H), 3.56−3.30 (m, 1H), 3.00−2.76 (m, 1H), 2.74−2.33
(m, 4H), 1.74 (ddt, J = 21.6, 6.5, 1.6 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 172.6, 172.4, 138.4, 138.3, 131.7, 131.2, 129.3,
129.2, 128.8, 128.7, 126.9, 126.8, 123.0, 122.7, 122.5, 119.2, 118.6,
51.9, 51.8, 39.9, 39.7, 38.8, 37.7, 37.0, 36.6, 35.3, 35.0, 17.9, 17.8.
HRMS (ESI−TOF) m/z: [M + Na]+ calcd for C16H19NO2Na
280.1313; found 280.1303.
General Procedure for the Synthesis of Products 15 and 17.
15 and 17 were prepared by analogous procedures as described above
for the related malononitrile and Meldrum’s acid substrates,
respectively. See the Supporting Information for thermal data related
to their Cope rearrangement.
16a. Isolated: 450 mg (>20:1 dr); yield: 90%; physical state: clear
oil; TLC: Rf = 0.30 (20% EtOAc in hexanes); purified using 20%
1
EtOAc in hexanes. H NMR (400 MHz, CDCl3): δ 5.78 (ddq, J =
15.2, 6.6, 0.8 Hz, 1H), 5.25 (ddq, J = 15.2, 8.6, 1.7 Hz, 1H), 4.20−
4.09 (m, 1H), 4.08−3.88 (m, 4H), 3.33 (ddt, J = 11.4, 5.6, 1.8 Hz,
1H), 3.02 (dddd, J = 14.8, 4.5, 2.6, 1.8 Hz, 1H), 2.56 (td, J = 14.4, 5.4
Hz, 1H), 2.43 (ddd, J = 14.8, 3.2, 1.9 Hz, 1H), 2.05 (ddt, J = 13.5, 5.6,
2.8 Hz, 1H), 1.96 (dd, J = 14.7, 5.6 Hz, 1H), 1.89−1.72 (m, 4H).
13C{1H} NMR (101 MHz, CDCl3): δ 178.5, 133.9, 121.9, 118.6,
111.0, 111.0, 105.9, 87.8, 65.6, 64.9, 45.2, 37.9, 36.9, 35.8, 28.8, 17.8.
HRMS (ESI−TOF) m/z: [M − H]− calcd for C16H16N3O2 282.1248;
found 282.1239.
16b. Crude material collected: 197.3 mg (>20:1 dr); conversion:
>95%; physical state: tan solid; TLC: Rf = 0.24 (30% EtOAc in
1
hexanes); material reported as is. H NMR (600 MHz, CDCl3): δ
5.29 (dq, J = 13.1, 6.4 Hz, 1H), 5.01 (dd, J = 15.1, 10.5 Hz, 1H), 4.09
(bs, 2H), 3.97−3.92 (m, 2H), 3.92−3.85 (m, 2H), 3.05 (dd, J = 11.2,
5.7 Hz, 1H), 2.79 (d, J = 14.9 Hz, 1H), 2.61 (td, J = 10.8, 2.8 Hz,
2H), 2.50 (td, J = 14.2, 5.4 Hz, 2H), 2.05 (d, J = 15.1 Hz, 1H), 2.00−
1.93 (m, 1H), 1.73 (dd, J = 14.6, 5.9 Hz, 1H), 1.71−1.64 (m, 1H),
1.63 (dd, J = 13.9, 4.5 Hz, 1H), 1.59 (d, J = 6.5 Hz, 3H), 1.46 (d, J =
12.9 Hz, 1H), 1.38 (s, 9H), 1.31−1.23 (m, 2H), 1.18−1.08 (m, 1H).
13C{1H} NMR (151 MHz, CDCl3): δ 185.2, 154.6, 129.4, 127.3,
111.7, 111.5, 106.5, 84.4, 79.2, 65.0, 64.1, 48.8, 43.2, 36.7, 35.3, 35.1,
31.0, 28.9, 28.3, 25.4, 17.7. HRMS (DART) m/z: [M + H]+ calcd for
C25H36N3O4 442.2700; found 442.2705, (DART) m/z: [M + NH4]+
calcd for C25H39N4O4 459.2966; found 459.2974.
18a. Isolated: 90 mg (>20:1 dr); yield: 99%; physical state:
yellow oil. TLC: Rf = 0.13 (20% EtOAc in hexanes); purified using
1
10% EtOAc in hexanes. H NMR (400 MHz, CDCl3): δ 7.32−7.27
(m, 4H), 5.56−5.34 (m, 2H), 4.55−4.48 (m, 1H), 4.15−4.04 (m,
2H), 3.90−3.80 (m, 3H), 3.74−3.59 (m, 1H), 2.64 (td, J = 14.0, 4.6
Hz, 1H), 2.14−2.08 (m, 1H), 1.80 (s, 3H), 1.77 (s, 3H), 1.66−1.63
(m, 2H), 1.59−1.43 (m, 3H), 1.29−1.22 (m, 1H). 13C{1H} NMR
(101 MHz, CDCl3): δ 181.2, 161.2, 160.9, 142.0, 132.3, 129.6, 128.9,
126.4, 117.2, 107.3, 103.9, 64.9, 64.1, 51.3, 44.1, 37.5, 36.4, 27.1, 27.0,
26.8, 18.1. HRMS (ESI−TOF) m/z: [M − H]− calcd for C24H26ClO6
445.1423; found 445.1430.
18b. Isolated: 16.8 mg (>20:1 dr); yield: 65%; physical state: pale
yellow oil; TLC: Rf = 0.40 (30% EtOAc in hexanes); purified using
1
25% EtOAc in hexanes. H NMR (600 MHz, CDCl3): δ 5.86−5.72
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(m, 1H), 5.27 (ddq, J = 15.2, 8.5, 1.6 Hz, 1H), 4.32 (dddd, J = 10.6,
5.4, 3.5, 1.7 Hz, 1H), 4.15 (dd, J = 10.6, 8.5 Hz, 1H), 4.10 (dt, J = 7.9,
6.5 Hz, 1H), 4.04 (ddd, J = 7.9, 6.5, 5.5 Hz, 1H), 3.99 (ddd, J = 7.8,
6.5, 5.5 Hz, 1H), 3.92 (dt, J = 7.7, 6.4 Hz, 1H), 3.70 (dddd, J = 13.7,
4.7, 3.0, 1.8 Hz, 1H), 2.45 (td, J = 13.7, 5.5 Hz, 1H), 2.36 (dt, J =
14.6, 3.3 Hz, 1H), 2.10 (ddt, J = 13.6, 5.7, 3.0 Hz, 1H), 1.95 (dd, J =
14.6, 5.5 Hz, 1H), 1.86 (td, J = 13.7, 4.8 Hz, 1H), 1.74 (d, J = 5.3 Hz,
6H), 1.63 (dd, J = 6.5, 1.7 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3): δ 175.4, 160.5, 160.5, 132.2, 123.3, 119.5, 118.9, 106.9,
104.3, 65.3, 64.7, 41.5, 37.9, 37.3, 27.2, 26.4, 18.0. HRMS (ESI−
TOF) m/z: [M + H]+ calcd for C19H27N2O6 379.1864; found
379.1881.
ACKNOWLEDGMENTS
■
This material is based upon work supported by the National
Science Foundation (NSF) under Grant No. 1844443 and the
National Institute of General Medical Sciences (NIGMS)
under Grant No. R35 GM137893-01. We thank the College of
Liberal Arts and Sciences and the Department of Chemistry at
the University of Florida for start-up funds. We thank the Mass
Spectrometry Research and Education Center and their
funding source, NIH S10 OD021758-01A1. J.N.S. acknowl-
edges the support of the National Institute of General Medical
Sciences of the National Institutes of Health under an F32
individual postdoctoral fellowship (F32GM122218). J.N.S.,
R.A.Y., and K.N.H. acknowledge support from the National
Science Foundation (CHE-1764328). Computational resour-
ces were provided by the UCLA Institute for Digital Research
and Education (IDRE).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02690.
Experimental procedures, HPLC traces, thermal data for
equilibrium studies related to the Cope rearrangement,
1H and 13C NMR reprints, and computational methods
(PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
K. N. Houk − Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095,
United States; orcid.org/0000-0002-8387-5261;
Email: houk@chem.ucla.edu
Alexander J. Grenning − Department of Chemistry, University
of Florida, Gainesville, Florida 32611, United States;
orcid.org/0000-0002-8182-9464; Email: grenning@
ufl.edu
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Ehsan Fereyduni − Department of Chemistry, University of
Florida, Gainesville, Florida 32611, United States
Ouidad Lahtigui − Department of Chemistry, University of
Florida, Gainesville, Florida 32611, United States
Jacob N. Sanders − Department of Chemistry and
Biochemistry, University of California, Los Angeles,
California 90095, United States; orcid.org/0000-0002-
2196-4234
Breanna M. Tomiczek − Department of Chemistry, University
of Florida, Gainesville, Florida 32611, United States
Michael D. Mannchen − Department of Chemistry, University
of Florida, Gainesville, Florida 32611, United States
Roland A. Yu − Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095,
United States
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