Maltol- And Allomaltol-Derived Oxidopyrylium Ylides: Methyl Substitution Pattern Kinetically Influences [5 + 3] Dimerization versus [5 + 2] Cycloaddition Reactions

Article abstract of DOI:10.1021/acs.joc.9b02137

Oxidopyrylium ylides are useful intermediates in synthetic organic chemistry because of their capability of forming structurally complex cycloadducts. They can also self-dimerize via [5 + 3] cycloaddition, which is an oft-reported side reaction that can negatively impact [5 + 2] cycloadduct yields and efficiency. In select instances, these dimers can be synthesized and used as the source of oxidopyrylium ylide, although the generality of this process remains unclear. Thus, how the substitution pattern governs both dimerization and cycloaddition reactions is of fundamental interest to probe factors to regulate them. The following manuscript details our findings that maltol-derived oxidopyrylium ylides (i.e., with ortho methyl substitution relative to oxide) can be trapped prior to dimerization more efficiently than the regioisomeric allomaltol-derived ylide (i.e., with a para methyl substitution relative to oxide). Density functional theory studies provide evidence in support of a sterically (kinetically) controlled mechanism, whereby gauche interactions between appendages of the approaching maltol-derived ylides are privileged by higher barriers for dimerization and thus are readily intercepted by dipolarophiles via [5 + 2] cycloadditions.

Full text of DOI:10.1021/acs.joc.9b02137

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Article
Maltol- and allomaltol-derived oxidopyrylium ylides:
Methyl substitution pattern kinetically influences [5 +
3] dimerization versus [5 + 2] cycloaddition reactions
Lauren P. Bejcek, Aswin K. Garimallaprabhakaran, Duygu M. Suyabatmaz,
Alexander Greer, William H. Hersh, Edyta M. Greer, and Ryan Patrick Murelli
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02137 • Publication Date (Web): 11 Oct 2019
Downloaded from pubs.acs.org on October 12, 2019
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Maltol- and allomaltol-derived oxidopyrylium ylides: Methyl
substitution pattern kinetically influences [5 + 3] dimerization versus
[5 + 2] cycloaddition reactions
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a,b
Lauren P. Bejcek,
Aswin K. Garimallaprabhakaran,a Duygu M. Suyabatmaz,a
Alexander Greer,a,b William H. Hersh,b,d Edyta M. Greer,c,* Ryan P. Murellia,b,*
a
Department of Chemistry, Brooklyn College, The City University of New York,
Brooklyn, NY, USA
b PhD Program in Chemistry, The Graduate Center of the City University of New York,
New York, NY, USA
c Department of Natural Sciences, Baruch College, City University of New York, New
York, NY, USA
d Department of Chemistry and Biochemistry, Queens College, City University of New
York, Queens, NY, USA
Contact emails – edyta.greer@baruch.cuny.edu and rpmurelli@brooklyn.cuny.edu
Abstract. Oxidopyrylium ylides are useful intermediates in synthetic organic chemistry
because of their capability of forming structurally complex cycloadducts. They can also
self-dimerize via [5 + 3] cycloaddition, which is an oft-reported side reaction that can
negatively impact [5 + 2] cycloadduct yields and efficiency. In select instances, these
dimers can be synthesized and used as the source of oxidopyrylium ylide, although the
generality of this process remains unclear. Thus, how the substitution pattern governs
both dimerization and cycloaddition reactions are of fundamental interest to probe factors
to regulate them. The following manuscript details our findings that maltol-derived
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oxidopyrylium ylides (i.e., with ortho methyl substitution relative to oxide) can be
trapped prior to dimerization more efficiently than the regioisomeric allomaltol-derived
ylide (i.e., with an para methyl substitution relative to oxide). DFT studies provide
evidence in support of a steric (kinetically) controlled mechanism, whereby gauche
interactions between appendages of the approaching maltol-derived ylides are privileged
by higher barriers for dimerization, and thus are readily intercepted by dipolarophiles via
[5 + 2] cycloadditions.
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Introduction
[5 + 2] Cycloaddition reactions between oxidopyrylium ylide intermediates and
dipolarophiles generate bicyclic compounds of synthetic use (i.e., 1 → 3, Scheme 1),
including highly functionalized natural products.1 Oxidopyrylium ylide intermediates
also have the capacity to dimerize through a [5 + 3] cycloaddition in their neutral form
(i.e., 1 → 4, Scheme 1),2,3 which is an important process that is in need of more study. A
mechanistic understanding of factors that influence oxidopyrylium ylide dimerization is
potentially of high value due to the difficulty in controlling the otherwise reactive state of
the neutral form.
Scheme 1. General representation of oxidopyrylium [5 + 2] cycloaddition chemistry, and the known
dimerization product of oxidopyrylium ylide 1.
Our lab has previously focused on intermolecular [5 + 2] cycloaddition reactions with
oxidopyrylium ylides generated via deprotonation of kojic acid (5)-derived methyl triflate
salts (Scheme 2), first described by Wender.3 During the course of these studies, it was
revealed that dimer 8 generally forms instantaneously upon treatment of base, even in the
presence of reactive dipolarophiles, but over time can convert into cycloadducts (i.e.,
10).4 While it has been proposed that the conversion of the oxidopyrylium dimer to
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cycloaddition products proceeds by way of cycloreversion back to oxidopyrylium ylides
(i.e., 7(-)),5 a confounding problem in the validation of this mechanistic hypothesis has
been the inability to directly detect the ylides due to their highly reactive nature. The
purification of oxidopyrylium dimer furthermore provides a source of oxidopyrylium
ylide free of the Brønsted acid and base, and has been advantageous in reaction
optimization6 and total synthesis efforts.7 However, it should be noted that high
temperatures and/or prolonged reaction times are needed which can present a potential
limitation. Thus, understanding how specific structural features influence relative rates of
oxidopyrylium ylide dimerization and cycloaddition reactions is of fundamental
importance.
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Scheme 2. Kojic acid-derived oxidopyrylium salt 7 and strategies for its usage in oxidopyrylium
cycloaddition chemistry
Herein we present experimental and theoretical results on factors that control the
dimerization versus cycloaddition behavior of regioisomeric maltol and allomaltol-
derived oxidopyrylium ylides. Specifically, we demonstrate that (i) maltol-derived
oxidopyrylium ylide (see 12(-) in Scheme 3 for details) is more rapidly trapped by
dipolarophiles, such as dimethyl acetylenedicarboxylate (DMAD, 16a), than the
allomaltol-derived ylide (7(-)); (ii) DFT calculations show that homo-dimerization of
maltol-derived oxidopyrylium ylide (12(-) → 13/14, Scheme 3) proceeds through a
concerted process, whereas homo-dimerization of allomaltol-derived oxidopyrylium ylide
(7(-) → 8) proceeds through a two-step process that is lower in energy; (iii) Kinetic
studies for the reaction between homodimers (8/13/14) and DMAD (16a) to form [5 + 2]
cycloaddition products reveal different kinetic profiles for the reaction with 8, and that
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with 13/14, but are each consistent with a mechanism involving full cycloreversion to the
oxidopyrylium ylide; and (iv) Studies with dipolarophiles are presented to gauge the [5 +
2] cycloaddition trapping efficiencies of the ylides prior to [5 + 3] dimerization.
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Results and Discussion.
Initial Observations Illustrating Dramatic Reactivity Differences Between Maltol
and Allomaltol-Derived Oxidopyrylium Ylides. Our studies began with an evaluation of
maltol-derived oxidopyrylium ylides (12(-), Scheme 3A), which were absent from the
literature with the exception of a single report by Li.8 Upon synthesizing the maltol-
derived oxidopyrylium salt (12) and treating it to triethylamine, we found that two dimers
formed in approximately 2:1 ratio (12 → 13 + 14, Scheme 3A). This result differed from
the analogous dimerization of allomaltol-derived salt 7, which led exclusively to a single
isomer, 8 (Scheme 3B). Both dimers 13 and 14 reacted with DMAD (16a) at higher
temperatures, affording oxidopyrylium cycloaddition product 15a, confirming that these
regioisomeric dimers could be used as an ylide source. However, the reactions were
noticeably more sluggish than was expected based on our experience with the analogous
reaction with dimer 8. In fact, the reaction between either dimer 13 or 14 with DMAD
(16a) only reached ~70% conversion after 8 h at 100 °C as compared to full conversion
within 5 min with dimer 8 in closely related studies (Scheme 3B).4 Consistent with these
findings, a competition experiments in which a 1:1 mixture of 8 and 13/14 heated in the
presence of 16a and monitored over time led first to formation 15b, followed by
formation of 15a. Therefore in order to promote a higher yielding process for the
cycloaddition with 13/14 and 16a, the reaction was carried out at elevated temperatures
(150 °C), which provided 15a in 95% yield after only 2 h (Scheme 3A).
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Scheme 3. Observed differences of [5 + 2] cycloadditions of (A) maltol and (B) allomaltol-derived
oxidopyrylium salts with dimethyl acetylenedicarboxylate (16a)
The more sluggish reactivity between dimer 13 and 14 with DMAD (16a) were
surprising to us, especially in light of findings by Li that a closely analogous reaction
between 12 and the presumably less reactive indole was completed within 7 h at room
temperature.8 Upon closer examination, when a CD3CN solution containing a mixture of
oxidopyrylium salt 12 and DMAD (16a) was subsequently treated with
N,N-diisopropylaniline, after only 30 minutes at room temperature, 15a was the major
product, and dimers 13 and 14 were only observed as minor products (12 → 15a,
Scheme 3A), more closely consistent with the Li studies. The result, however, was highly
contradictory to our experience with regioisomeric salt 7, where dimer 8 is almost always
observed as the major product upon addition of base in the presence of dipolarophiles,
and over time or at elevated temperature converts to cycloaddition products (7 → 8 →
15b, Scheme 3B). Likewise, competition experiments in which a 1:1 mixture of 7 and 12
in the presence of 16a are treated to N,N-diisopropylaniline and monitored over time via
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1H NMR, resulted in only the appearance of dimer 8 (from 7) and DMAD cycloadduct
15a (from 12).
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Given these findings, the dimerization processes were evaluated in the absence of
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DMAD (16a).
Consistent with prior experiences,4 treatment of salt 7 to
N,N-diisopropylaniline led to complete conversion to dimer 8 within 5 min. On the other
hand, when salt 12 was treated to identical conditions, conversion to 13 and 14 took
upwards of 7 hours, and when monitoring the reaction by 1H NMR, no signals were ever
observed that could be attributed to ylide 12(-). We initially hypothesized that these
slower conversion rates were the result of slower deprotonation, possibly due to an
increase in sterics due to the close proximity of the proton to the methyl group of 12.
However, the steric hypothesis was disproven since switching to the less sterically
demanding base, N,N-dimethylaniline slowed the consumption of 12 even more-so,
consistent with the lower pKa of N,N-dimethylaniline.9 Likewise, N,N-dimethylaniline
slowed down the conversion of salt 7 to dimer 8 to a rate more comparable with the
rate that N,N-diisopropylaniline promotes the conversion of 12 to 13 and 14 (Scheme
4A). We thus treated a solution of 7 and DMAD (16a) in CD3CN to N,N-dimethylaniline
to assess whether greater trapping efficiency could be achieved with a slower
deprotonation. However, when viewed at only partial conversion of salt 7 (15 min),
dimer 8 remained the major product (Scheme 4B).
Scheme 4. Effects of base on salt conversion and cycloaddition trapping efficiency. (A) Conversion
over time of salt 12 with N,N-diisopropylaniline and salt 7 with N,N-dimethylaniline. (B) Analysis of the
ratio between cycloaddition and dimerization products for the reaction between 7 and DMAD (16a) when
initiated by N,N-dimethylaniline, as observed at partial conversion.
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The above experimental results made it evident that the differences in DMAD (16a)
trapping efficiency from salt 7 and 12 prior to dimerization could not be fully explained
by simple differences in rates of deprotonation, and thus these differences might exist
after the deprotonation step and involve relative reactivities of the ylides. Thus, we turned
to DFT calculations to study the relative dimerization and cycloaddition reactions from
7(-) and 12(-).
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DFT Calculations. B3LYP/6-31G(d,p) calculations were employed here. Similar
DFT calculations have been used to assess the tendency for compounds to dimerize,10 and
in cycloadditions of butadiene with oxidopyrilium ylides.11 To explore the bimolecular
pathways (Scheme 5), we have located structures on the potential energy surface (PES)
for the dimerization of maltol 12(-) and allomaltol 7(-) oxidopyrylium ylides. Our
calculations focused on the neutral forms of maltol and allomaltol oxidopyrylium ylides
since these are expected to give rise to the dimers. Since 7(-) and 12(-) are structural
isomers, their relative energies can be readily compared. The global minimum is the
complex of 12(-).
.
Scheme 5A shows the formation of dimer 8 from the allomaltol-derived oxidopyrylium
ylide 7(-), which proceeds through a step-wise process. This process involves an initial
carbon-carbon bond formation via an aldol-like process between the -carbon of the
embedded enolate of one ylide, and the more sterically unencumbered electrophilic
carbon of the other. The reaction ΔH‡ is 8.3 kcal/mol (compared to 7(-)), and leads to
the second step, where a more sterically encumbered carbon creates the second carbon-
carbon bond of dimer 8. In the formation of dimer 8, there is a methyl-methoxy gauche
interaction, but it is a lower in energy likely due to the fact that it is an intermolecular
process (TS-2, Figure 1). The formation of dimer 13 from maltol oxidopyrylium
ylide 12(-), on the other hand, proceeds through an asynchronous concerted process
(Scheme 5B). The dimerization of 12(-) is higher in energy than the dimerization
of 7(-) due to an unfavorable methyl-methyl gauche interaction, producing a ~2 kcal/mol
higher transition state energy (i.e., ΔH‡ of 11.6 kcal/mol) than that of 7(-) (TS-3, Figure
1). An identical ΔH‡ of 11.6 kcal/mol energy barrier exists in the transition state to
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dimer 14. Even though sterics of a methoxy group are generally lower in energy than a
methyl group, this specific methoxy-methyl gauche interaction appears to have added
steric strain, where the methyl group of the methoxy extends over the incipient carbonyl
group (TS-4, Figure 1). This explains why both dimers of 12(-) are formed, in contrast to
the selective [5 + 3] dimerization of 7(-).
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A
B
2.89
2.22
2.92
2.11
2.84
TS-3
TS-4
1.58
11.6
TS-1
2.31
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OMe
9.5
O
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OMe
TS-2
[0.0]
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Me
-3.0
O
-3.6
12(-)
O
Me
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-15.0
Me
O
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O
Me
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O
O
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OMe
O
Me
O
Me
7(-)
OMe
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Me
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12(-)
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O
8
O
O
OMe
OMe
14
13
Scheme 5. Computed potential energy surface of maltol and allomaltol oxidopyrylium ylides 7(-) and
12(-). The computed potential surface uses two molecules of 7(-) in A, and two molecules of 12(-) in B.
Figure 1. Top perspective of transition states to dimerization to highlight steric interactions. (A)
Graphical perspective of the second bond forming reaction in production of 8, (TS-2), and the concerted
formation of dimer 13 and 14 demonstrating energetically costly steric interactions. (TS-3 and TS-4). (B)
Transition state perspectives re-drawn and color coordinated for visual clarity.
The cycloaddition reactions between DMAD (16a) and either 7(-) or 12(-) were
fairly analogous energetically, and each was predicted to proceed through a concerted,
asynchronous pathway. The transition state between DMAD and 12(-) was only slightly
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favored over that between DMAD and 7(-) (11.7 vs. 12.9 kcal/mol, Scheme 1S, see SI
section for details). Furthermore, cycloaddition products were thermodynamically
favored over dimer products by approximately 40 kcal/mol in both cases, consistent with
the observations that, with enough time and energy, all of the dimers investigated can be
converted to their respective oxidopyrylium [5 + 2] cycloaddition products.
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Kinetic Studies. Kinetics experiments were carried out as a means to evaluate the
relative transition state energy barriers for dimerization and cycloaddition processes.
Drawing inspiration and precedence from classic kinetic studies on the reaction between
dialkylborane dimers and alkenes by Brown et al.,12 steady state approximation was
employed to evaluate the reaction between oxidopyrylium dimers (8/13/14) and DMAD
(16a) (8 + 16a → 15b or 13/14 + 16a → 15a, Scheme 6). In this way, the kinetics are
fixed on the key reactions of interest – namely, the [5 + 2] cycloaddition (k2) and
dimerization/cycloreversion (k3/k-3) (Scheme 6). Assuming the energy barrier for
dimerization of 12(-) is higher than the energy barrier for the cycloaddition reaction with
DMAD (16a) to an extend such that 1/2k2[16a] >> k3[12(-)], the reaction should exhibit
first-order kinetics, as represented by the equation −d[13]/dt = k1[13]. Conversely, if the
cycloaddition step between 7(-) and DMAD (16a) is higher in energy than the
dimerization of 7(-) such that 1/2k2[16a] << k3[7(-)], than the reaction should exhibit
three-halves-order kinetics, as represented by the equation –d[8]/dt = k3/2[8]1/2[16a].
Scheme 6. Overview of competing cycloaddition and dimerization pathways from 7/12, also
illustrating conversion of 8/13/14 to 15a/15b.
To evaluate the kinetics experimentally, conversion of 8 and 13 were monitored over
time with an excess of DMAD (16a), and the resultant plots were evaluated for best fit
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(Figure 2A).13 Consistent with the anticipated kinetics, conversion of 8 fit best to half-
order kinetics ([8]t1/2 vs. time), whereas conversion of 13 fit best to first order kinetics
(ln[13]t vs. time). We also carried out experiments in the inverse, with an excess of the
dimers (Figure 2B). In the presence of dimer 13, the rate of conversion of DMAD (16a)
stayed consistent as the concentrations decreased, in line with 0th order kinetics.
However, in the presence of dimer 8, the rate changed as the concentration of DMAD
(16a) changed, fitting best to 1st order kinetics (ln[16a]t vs. time). Experiments
performed with 14 were also consistent with those performed with 13 (See supporting
information). Thus, these studies provided experimental evidence that in the reaction
between allomaltol-derived oxidopyrylium ylide 7(-) and 16a, dimer 8 is the kinetic
product, helping explain the difficulty of intercepting 7(-) with DMAD (16a).
Conversely, the studies also provided experimental evidence that in the reaction between
maltol-derived oxidopyrylium ylide 12(-) and 16a, cycloaddition product 15a is the
kinetic product, which explains why 12(-) can be successfully intercepted with DMAD
(16a).
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Figure 2. Graphs from Kinetics Studies. (A) The concentration of dimer 8 and 13 over time with an
excess of 16a. (B) 16a in an excess of dimer 8 and 13.
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Dipolarophile Dependence. Both DFT calculations and kinetics experiments helped
explain why DMAD (16a) is trapped more efficiently by 12(-) than by 7(-). We next
wanted to gauge how their relative trapping efficiency might extend to other
dipolarophiles. For these studies, we added N,N-diisopropylaniline to a solution of
CD3CN containing oxidopyrylium salts 7 and 12 and a panel of dipolarophiles of varying
reactivity (16a-d), and monitored reaction progress by 1H NMR (Scheme 7).
Phenylacetylene (16d) is known to react more sluggishly with 7(-) than DMAD (16a).4
Transition state energy barriers were thus computed for the reaction of 16d with 7(-) to
form 15g (ΔH‡ = 16.3 kcal/mol, Scheme 2S, see SI section for details) and for the reaction
of 16d with 12(-) to form 15h (ΔH‡ = 17.4 kcal/mol, Scheme 2S, see SI section for details).
As these energy barriers are each higher than their respective dimerization energy
barriers, dimerization products should be the kinetic products in both instances.
Consistent with this hypothesis, when N,N-diisopropylaniline was treated to a mixture of
16d and either salt 7 or 12, upon complete consumption of salts, only dimerization
products were observed (see entry for products 15g/h).
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Scheme 7. Products to dimer ratio upon oxidopyrylium ylide formation in the presence of a range of
dipolarophiles. Yields calculated by 1H NMR integration using an internal standard following full
consumption of salt.
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For a more reactive dipolarophile, we turned to the highly electrophilic 4-phenyl-1,2,4-
triazole-3,5-dione (PTAD, 16b, see entry for products 15c/d).14 As anticipated, very low
transition state energy barriers were calculated for the reaction between 16b and both 7(-)
(ΔH‡ = 2.7 kcal/mol) and 12(-) (ΔH‡ = 3.1 kcal/mol, Scheme 3S, see details in the SI
section). As these barriers were each substantially lower than those of their respective
dimerization reactions, 15c and 15d would both be expected to be the kinetic products.
Consistent with this, when N,N-diisopropylaniline was treated to a mixture of 16b and
either salt 7 or 12, no dimer was observed and the [5 + 2] cycloaddition products 15c and
15d predominated. These two sets of experiments demonstrated that with the more
extremes on the dipolarophile reactivity spectra, trapping efficiency of the two salts are
similar. However, when these experiments were performed with the more intermediately
reactive dipolarophile, methyl propiolate (16c, see entry for products 15e/f), differences
in the trapping efficiencies of 7(-) and 12(-) returned. Specifically, when salt 7 was treated
to the base in the presence of 16c, only dimer 8 was observed, whereas significant
amounts of product 15e were observed in the analogous reaction with 12.
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Mechanistic Interpretation and Implications. Oxidopyrylium ylides 7(-) and 12(-)
can undergo both [5 + 3] dimerization and [5 + 2] cycloaddition chemistry to generate
dimers (8, 13, 14) or cycloaddition products (i.e., 15a/b), respectively. The dimerization
to 8 and 13/14 is reversible and leads back to the ylides, which can then convert further to
the thermodynamically stable oxidopyrylium cycloaddition products, 15a and 15b, when
heated in the presence of DMAD (16a). Instead of the dimer reacting directly with the
dipolarophile, the kinetic and computational results support a mechanism whereby dimer
conversion to cycloaddition products proceeds through cycloreversion of the dimers to
oxidopyrylium ylides followed by a cycloaddition reaction. Kinetics for these two
reactions are different, however. Kinetics from the reaction from dimer 8 and DMAD
(16a) is consistent with a mechanism wherein the transition state energy for [5 + 3]
cycloreversion/dimerization is lower than that of the [5 + 2] cycloaddition reaction, and
that from 13/14 consistent with one where the transition state for [5 + 3]
cycloreversion/dimerization is higher in energy than the [5 + 2] cycloaddition step.
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DFT studies were consistent with these trends, revealing that the transition state barrier
for dimerization of 12(-) is higher in energy than that of 7(-) (Scheme 5), and thus 8 is the
kinetic product relative to 15a, whereas 15b is the kinetic product relative to 13/14. The
DFT studies indicate that these energy differences are the result of unavoidable steric
interactions in the transition state towards both dimer 13 and 14, which alter the
mechanism for the different dimerization reactions. The implications to these studies are
that by positioning groups ortho to the oxide (e.g. 12(-)), the transition state barrier
towards dimerization can increase, and improve the success rate of trapping the ylide
with a dipolarophile prior to self-dimerization. One could anticipate based upon these
results that by increasing the size of these groups, rate of dimerization will be slowed
even further and allow for even more efficient [5 + 2] trapping. Indeed, 2,4,6-
triphenylpyrylium-3-oxide is one of the few oxidopyrylium ylides to ever be observed
experimentally and does not dimerize,15 which may be why it reacts with an extremely
broad range of dipolarophiles.16 In the current studies, dramatic differences in trapping
efficiency were observed with DMAD (16a) and methyl propiolate (16c). However, the
more reactive dipolarophile PTAD (16b) efficiently intercepted both ylides, whereas the
less reactive dipolarophile phenylacetylene (16d) could not intercept either ylide. Thus,
further structure-activity relationships with a broader range of both oxidopyrylium ylides
and dipolarophiles is warranted.
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Conclusion
Synthetic, kinetic, and theoretical approaches have been developed to probe
oxidopyrylium ylide reactivity in self-dimerization and cycloaddition reactions. We find
the following results: (i) maltol- and allomaltol-derived oxidopyrylium salts serve as
precursors to their corresponding oxidopyrylium ylides 7(-) and 12(-), which themselves
serve as intermediates in both self-dimerization or cycloaddition reactions; (ii) DFT
calculations provide valuable insight on the dimerization mechanism of these two
oxidopyrylium ylides where gauche methyl/methyl or methyl/methoxy interactions favor
the dimerization in a kinetically not thermodynamically controlled fashion compared to
the [5 + 2] cycloaddition selectivity; (iii) Kinetics for the reaction between dimethyl
acetlylenedicarboxylate (16a) and oxidopyrylium dimers suggest that the rate limiting
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step with dimer 8 is the cycloaddition reaction; in contrast, the reaction with dimer 13 or
14 is consistent with a mechanism where the rate limiting step is the cycloreversion to
ylide 12(-); (iv) While oxidopyrylium ylides 7(-) and 12(-) have very different trapping
efficiency profiles with DMAD (16a) and methylpropiolate (16c), only cycloaddition
products form in the presence of the more reactive PTAD (16b), and only dimers form in
the presence of less reactive phenylacetylene (16d). These studies provide insight into
how differences in structure of the oxidopyrylium ylides such as the placement of
appendages can lead to significantly different reactivity behaviors. Future studies
combining synthetic, kinetic, and theoretical studies across a broader range of
oxidopyrylium ylides should further enhance our understanding of these systems, and
help inform future synthetic strategies employing oxidopyrylium cycloaddition and
dimerization reactions. For example, the decomposition of homodimers is a retro reaction
of “masked” neutral oxidopyrylium ylide monomers, and is a base-free strategy that could
be valuable for some reactions. In contrast to the reactivity of DMAD with dimers 8,
13 and 14, Hendrickson’s early work described how the reaction between the dimer
of an unsubstituted 3-oxidopyrylium ylide and DMAD only forms trace products,
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o
even at 200 C.2b Thus, there appear to be structural advantages to dimers 8, 13,
and 14 that allow them to behave as oxidopyrylium ylide sources. It seems
reasonable to hypothesize that the OMe plays an important role in this reactivity by
both enhancing the nucleophilicity of the ylides and destabilizing the ground state of
8 and 14 through the gauche interactions it presents. Further studies are underway
to assess the importance of the OMe group for efficient dimerization reversibility,
and whether other oxidopyrylium ylide dimers without OMe groups may also
behave as ylide sources. In other instances, dimerization may pose greater technical
challenges, and knowledge of how to effectively trap out ylides prior to dimerization will
be valuable.
Experimental Section
General Information. All starting materials and reagents were purchased from
commercially available sources and used without further purification, with the exception
of CH2Cl2, which was purified on a solvent purification system prior to reactions. 1H, and
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13C NMR shifts were measured using the solvent residual peak as the internal standard
and reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d =
doublet, t = triplet, dd = doublet of doublets, q = quartet, m = multiplet), coupling
constant (Hz), integration. Infrared (IR) spectral bands are characterized as broad (br),
strong (s), medium (m), and weak (w). Mass spectra were recorded on a spectrometer by
the electrospray ionization (ESI) technique with a time-of-flight (TOF) mass analyzer.
Microwave reactions were performed via the Biotage Initiator EXP US (manufacturer #:
355302)(external IR temperature sensor) in a sealed vessel. Where noted, reaction
products were purified via silica gel chromatography using a Biotage Isolera Prime, with
Biotage® SNAP Ultra 10 g or 25 g cartridges, in a solvent system of ethyl acetate
(EtOAc) in hexane.
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Synthesis and Characterization of Maltol-Derived Oxidopyrylium Salt. 3-hydroxy-
4-methoxy-2-methylpyrylium trifluoromethanesulfonate (12). To a solution of maltol
(11, 5g, 0.0396 mol) in CH2Cl2 (10 mL) was added methyl trifluoromethanesulfonate
(MeOTf, 6.5 mL, 0.0594 mol). The reaction was allowed to stir at reflux for 4 h, cooled
to ambient temperature, and then evaporated under reduced pressure to yield 12 as solid
white crystals (6.5 g, 54% yield), with a melting point range of 99-102 °C. IR (thin film,
KBr): 3088 (w) 1634 (s) 1554 (w) 1497 (m) 1438 (w) 1258 (b) 1164 (s) 1069 (w) 1033
1
(s) 962 (w) 903 (w) 827 (w) 750 (b) 636 (s) cm-1. H NMR (400 MHz, CD3CN) δ 8.80
13
(d, J = 5.2 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 4.31 (s, 3H), 2.68 (s, 3H). C{1H} NMR
(101 MHz, CD3CN) δ 168.8, 166.4, 161.2, 142.9, 108.5, 60.7, 16.3.
Synthesis and Characterization of Maltol-Derived Oxidopyrylium Dimers (13) and
(14). In a round bottom flask, triflate salt 12 (0.1 g, 0.345 mmol, 1 eq), was suspended in
CH2Cl2 (3 mL, 0.1M). Triethylamine (96 L, 0.690 mmol, 2 eq) was slowly added to the
reaction mixture, at which time the solid slowly dissolved. The reaction mixture was
allowed to stir for 2 h at room temperature, and was then quenched with saturated
aqueous ammonium chloride (5 mL). The organic layer was isolated and the aqueous
layer was extracted with CH2Cl2 (3 x 10 mL). Combined organics were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude material was
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purified by chromatography (Biotage Isolera Prime, SNAP 12 g silica gel, 18 cm x 1.8
cm, solvent gradient: 0-25% EtOAc in hexanes (500 mL). Two products were separated
and product fractions were concentrated to yield 13 (22 mg, 0.0786, 45% yield) and 14
(12 mg, 0.0429, 25% yield), both isolated as white solids. (±)-(1R,2S,6S,7R)-6,9-
dimethoxy-1,2-dimethyl-3,11-dioxatricyclo[5.3.1.12,6]dodeca-4,8-diene-10,12-dione
(13). Mp: 129-132 °C. Rf = 0.14 in 20 % ethyl acetate in hexanes. IR (ATR, ZnSe) 3090
(w), 3002(w), 2941(br), 2834 (br), 1742(s), 1699(s), 1626(s), 1455(w), 1358(m),
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1258(m), 1170(s), 1139(s), 1066(s), 1036(m), 914(m), 841(w), 789(w). H NMR (400
MHz, CDCl3) δ 6.67 (d, J = 5.9 Hz, 1H), 6.01 (d, J = 5.1 Hz, 1H), 5.02 (d, J = 5.9 Hz,
1H), 4.49 (d, J = 5.1 Hz, 1H), 3.63 (s, 3H), 3.49 (s, 3H), 1.55 (s, 3H), 1.25 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 199.5, 188.8, 149.9, 148.2, 113.0, 100.5, 92.4, 87.6,
+
86.3, 77.4, 55.5, 54.1, 17.3, 14.7. HRMS (ESI-TOF) m/z: [M+H]+ calc’d for C7H9O3 :
141.0473 Found: 141.0561. (±)-(1R,2R,6R,7R)-6,9-dimethoxy-2,7-dimethyl-3,11-
dioxatricyclo[5.3.1.12,6]dodeca-4,9-diene-8,12-dione (14). Mp: 159-159 °C. Rf = 0.14
in 25 % ethyl acetate. IR (ATR, ZnSe) 3090 (w), 3002(w), 2941(br), 2834 (br), 1742(s),
1699(s), 1626(s), 1455(w), 1358(m), 1258(m), 1170(s), 1139(s), 1066(s), 1036(m),
1
914(m), 841(w), 789(w). H NMR (400 MHz, CDCl3) δ 6.69 (d, J = 6.0 Hz, 1H), 5.64
(d, J = 5.2 Hz, 1H), 4.92 (d, J = 6.0 Hz, 1H), 4.74 (d, J = 5.2 Hz, 1H), 3.60 (s, 3H), 3.43
(s, 3H), 1.45 (s, 3H), 1.39 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 199.3, 188.5,
150.7, 148.3, 109.0, 98.3, 89.7, 87.8, 86.0, 80.0, 55.4, 54.5, 17.1, 17.0. HRMS (ESI-
+
TOF) m/z: [M+H]+ calc’d for C7H9O3 : 141.0473 Found: 141.0838. Stereochemistry of
13 and 14 were determined by X-ray crystal analysis. See X-ray section, below, for
details.
Synthesis of New Oxidopyrylium [5 + 2] Cycloadducts for Characterization.
Cycloadducts 15b, 15f and 15h were synthesized previously.4 Compounds 15a, 15c, 15d,
15e, and 15g were synthesized as follows to provide characterization data in support of
1H NMR yields described in Scheme 7.
(±)-Dimethyl (1S,5S)-3-methoxy-5-methyl-4-oxo-8-oxabicyclo[3.2.1]octa-2,6-diene-
6,7-dicarboxylate (15a). To a solution of 13/14 (20 mg, 0.0714mmol, 1 eq) in CDCl3
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(1 mL, 0.9 M) was added dimethyl acetylenedicarboxylate (16a, 100 L, 0.814
mmol, 11 eq). The reaction was subjected to microwave irradiation at 150 C for 2
h, and immediately purified by chromatography (Biotage Isolera Prime, SiliCycle
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SiliaSep 25 g silica gel, 40-63 µm 60 Å, solvent gradient: 0-25% EtOAc in hexanes (500
mL)). Product fractions were concentrated en vacuo to yield 15a as a pale, yellow oil (38
mg, 95% yield). Rf = 0.53 in 25% ethyl acetate. IR (thin film, KBr): 2956 (w), 2843
(w), 1716 (s), 1654 (w), 1614 (m), 1438 (m), 1379 (w), 1281 (b), 1146 (w), 1069 (s),
1005 (m), 933 (w), 902 (w), 878 (w), 847 (w), 812 (w), 787 (w), 766 (w), 700 (w), 6309
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(w) cm-1. H NMR (400 MHz, CDCl3) δ 6.15 (d, J = 4.9 Hz, 1H), 5.39 (d, J = 4.9 Hz,
1H), 3.79 (d, J = 6.4 Hz, 6H), 3.56 (s, 3H), 1.59 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 188.2, 163.1, 162.1, 146.5, 146.4, 143.1, 114.4, 94.0, 78.2, 55.1, 52.8. 52.8,
+
16.2. HRMS (ESI-TOF) m/z: [M+H]+ calc’d for C13H15O7 : 283.0812 Found: 283.0817
(±)-(5R,9S)-7-methoxy-5-methyl-2-phenyl-1H,5H-5,9-epoxy[1,2,4]triazolo[1,2-
a][1,2]diazepine-1,3,6(2H,9H)-trione (15c). To a solution of 12 (50 mg, 0.172mmol, 1
eq) and 4-Phenyl-1,2,4-triazole-3,5-dione (16b, 60 mg, 0.344 mmol, 2 eq) in CD3CN
(600 L, 0.3M) was added N,N-diisopropylaniline (29 L, 0.2068 mmol, 1.2 eq). The
reaction stirred for 5 minutes and was then immediately purified by chromatography
(Biotage Isolera Prime, SiliCycle, SiliaSep 25 g silica gel column, 40-63 µm 60 Å,
solvent gradient: 0-25% EtOAc in hexanes (500 mL)). Product fractions were
concentrated en vacuo to yield 12 as a white solid (39 mg, 72% yield). Mp: 65-70 °C. Rf
= 0.50 in 25% in ethyl acetate. IR (thin film, KBr): 3429 (br), 1731 (s), 1633 (w), 1498
(w), 1399 (m), 1363 (w), 1232 (w), 1148 (w), 1075 (m), 778 (w), 690 (w) cm-1. 1H NMR
(400 MHz, CDCl3) δ 7.51 – 7.38 (m, 5H), 6.34 (d, J = 5.0 Hz, 1H), 6.11 (d, J = 5.0 Hz,
1H), 3.70 (s, 3H), 1.96 (s, 3H).13C{1H} NMR (101 MHz, CDCl3) δ 182.2, 156.5, 154.87,
150.9, 130.9, 129.5, 129.1, 125.6, 109.8, 96.8, 83.4, 55.9, 15.2. HRMS (ESI-TOF) m/z:
+
[M+H]+ calc’d for C15H14N3O5 : 316.0928 Found: 316.0928.
Synthesis
of
(5R,9S)-7-methoxy-9-methyl-2-phenyl-1H,5H-5,9-
epoxy[1,2,4]triazolo[1,2-a][1,2]diazepine-1,3,6(2H,9H)-trione (15d) in the presence
of excess salt*: To a mixture of oxidopyrylium salt 12 (20 mg, 0.0689 mmol) and 4-
phenyl-1,2,4-triazoline-3,5-dione (16b, 8 mg 0.0457 mmol) in DCM (1 mL, 0.0457 M)
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was added triethylamine (12 L, 0.0860 mmol). The reaction was stirred for 5 minutes at
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room temperature and subsequently washed with aqueous ammonium chloride (3 x 3
mL). The organic layer was isolated and the aqueous layer was extracted with CH2Cl2 (3
x 5 mL). Combined organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure to yield a mixture of dimer 8, cycloadduct 15d, and PTAD (16b).
15d is unstable to chromatography and attempts at crystallization were unsuccessful. It
was thus characterized as a mixture of the three. See supporting information for further
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details. H NMR (400 MHz, CD3CN) δ 7.59 – 7.35 (m, Ar)*, 6.28 (s, 1H), 5.86 (s,1H),
3.66 (s, 3H), 2.07 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 182.5, 157.3, 155.8,
150.5, 125-135 (Ar),* 116.6, 89.9, 56.5, 55.3, 21.1. *Aromatic regions undefined due to
presence of PTAD overlapping in the aromatic region. HRMS (ESI-TOF) m/z: [M+H]+
+
calc’d for C15H14N3O5 : 316.0928 Found: 316.0928.
(±)-Methyl (1S,5S)-3-methoxy-1-methyl-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6-
carboxylate (15e). To a solution of 14 (25 mg, 0.0893mmol, 1 eq) in CDCl3 (1 mL,
0.9M) was added methylpropiolate (16c, 80 L, 0.893 mmol, 10 eq). The reaction was
subjected to microwave irradiation at 100 C for 2 h and then purified by
chromatography (Biotage Isolera Prime, SiliCycle SiliaSep 25 g silica gel column, 40-63
µm 60 Å, solvent gradient: 0-25% EtOAc in hexanes (500 mL)). Product fractions were
concentrated en vacuo to yield 15e as a yellow oil (18 mg, 60% yield). Rf = 0.20 in 25%
ethyl acetate. IR (thin film, KBr): 3448 (br), 2956 (w), 2358 (w), 1716 (s), 1654 (w),
1614 (m), 1438 (m), 1336 (m), 1379 (w), 1227 (w) 1281 (br), 1146 (w), 1069 (s), 1033
1
(m), 933 (w), 902 (w), 878 (w), 847 (w), 812 (w) cm-1. H NMR (400 MHz, CDCl3) δ
6.88 (s, 1H), 6.22 (d, J = 4.9 Hz, 1H), 5.41 (d, J = 4.9 Hz, 1H), 3.81 (s, 3H), 3.57 (s, 3H),
1.59 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 190.6, 163.1, 148.2, 146.5, 142.2,
+
115.6, 93.5, 78.1, 55.0, 52.4, 17.1. HRMS (ESI-TOF) m/z: [M+H]+ calc’d for C11H13O5 :
225.0757 Found: 225.0751.
(±)-(1S,5S)-3-methoxy-1-methyl-6-phenyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one
(15g). To a solution of 14 (25 mg, 0.0893 mmol, 1 eq) in CDCl3 (1 mL, 0.9 M) was
added phenylacetylene (16d, 100 L, 0.911 mmol, 11 eq). The reaction was
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subjected to microwave irradiation at 120 C for 8 h and then purified by
chromatography (Biotage Isolera Prime, SiliCycle SiliaSep 25 g silica gel column, 40-
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63 µm 60 Å, solvent gradient: 0-25% EtOAc in hexanes (500 mL)). Product fractions
were concentrated en vacuo to yield 14 as a yellow oil (7 mg, 16% yield). Rf = 0.13 in 25
% in ethyl acetate. IR (thin film, KBr): 3446 (br) 2933 (w) 1705 (s) 1614 (m) 1446 (w)
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1343 (w) 1242 (w) 1063 (br) 905 (w) 852 (w) 691 (w) 649 (w) cm-1. H NMR (400
MHz, CDCl3) δ 7.42 – 7.35 (m, 5H), 6.30 (d, J = 4.9 Hz, 1H), 6.27 (s, 1H), 5.58 (d, J =
4.8 Hz, 1H), 3.55 (s, 3H), 1.63 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 191.6,
155.8, 147.4, 131.9, 129.4, 129.1, 126.0, 124.0, 114.9, 93.1, 79.1, 55.0, 17.6. HRMS
(ESI-TOF) m/z: [M+H]+ calc’d for C15H15O3 : 243.1016 Found: 243.1001.
+
Evaluation of Product versus Dimer Upon Full Conversion of Oxidopyrylium Salt.
In a small vial, salt (7 or 12) (5mg, 0.0172 mmol, 1 eq), alkyne (16a-d) (0.172 mmol, 10
eq) in 600 L of CD3CN was added N,N-diisopropylaniline (4 L, 0.0207 mmol, 1.2
1
eq). The reaction was monitored over time by H NMR, and yields were
1
calculated using H NMR integration based upon known amount of 3,5-
ditertbutyltoluene standard in the reaction mixture. For conversion to known
1
compounds 15b, 15f, 15h, and 8, H NMR of reactions were compared to
literature spectra.4
Rate Studies. All rate studies were conducted in Wilmad® low pressure/vacuum NMR
tube where concentrations of substrates were determined via known amount of added
internal NMR standard, 3,5-Di-tert-butyltoluene. For conversion to known compound
15b, H NMR spectra were compared to literature spectra.4 All experiments were
1
run at least twice to obtain consistent data sets.
General procedure for excess of 16a with dimers 8, 13, and 14 separately: To dimer
(8, 13, or 14) (3 mg, 0.01 mmol) in 600 L of deuterated toluene was added 16a
(26.5 L, 0.2 mmol, 20 eq). The reaction was heated in an oil bath (100 C for
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dimers 13 and 14, 70 C for dimer 8) and monitored to near completion via
internal NMR standard (3,5-di-tert-butyltoluene).
7
General procedure for excess of dimers 8,413, and 14 separately with 16a: To dimer
(8, 13, or 14) (15 mg, 0.05 mmol) in 600 L of deuterated toluene was added
16a (1.3 L, 0.01 mmol). The reaction was heated in an oil bath (100 C for
dimers 13 and 14, 70 C for dimer 8) and monitored to near completion via
internal NMR standard (3,5-di-tert-butyltoluene).
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Computational Methods. Optimizations, frequency calculations, the intrinsic reaction
coordinate calculations were performed with Gaussian 09 (revision D.01)17 at the
3LYP/6-31G(d,p) level of theory18 and visualized with Gaussview 5.0.19 These
calculations yielded results in reasonably good agreement with experiment. The
energetics are reported as the thermal enthalpies. For the potential energy surface (PES)
in Scheme 5, frequency calculations established the nature of the stationary point
obtained. Vibrational analyses showed that TS-1—TS-4 species were transition
structures, while 7(-), 8, 12(-), 13, and 17 minima. The intrinsic reaction coordinate
(IRC)20 calculations were used to verify the transition structures TS-1—TS-4.
X-Ray. The structures of 8, 13, and 14 are the first to be determined for these tricyclic
heterocycles, and they confirm the proposed structures. Crystals were grown using vapor
diffusion technique, using minimal ethyl acetate to solubilize dimers and hexanes as the
outer solvent. The crystals of 13 and 14 appeared to be split crystals, most likely with
more than two domains, giving rise to relatively high residuals due to overlapping peaks
and in addition 13 was not strongly diffracting. The X-ray intensity data were measured
on a Bruker Smart Breeze CCD system equipped with a graphite monochromator at
100(2) K, cooled by an Oxford Cryosystems 700 Series Cryostream. A total of 1464
frames were collected and were integrated with the Bruker SAINT software package,
using a narrow-frame algorithm. Data were corrected for absorption effects using the
multi-scan method (SADABS or TWINABS). The structures were solved and refined
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using the Bruker SHELXTL Software Package. All data and methods may be found in
the cif files included in the Supporting Information. Briefly, refinement of 8 was routine
and 13 was refined as a 2-component twin. Compound 14 had to be refined as a 2-
component twin but the second domain refined to just 2%, and it also exhibited a ~1:1
disorder for molecule 2 of the two in the asymmetric unit, for one methoxy methyl and
one methyl group.
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Cambridge Crystallographic Data Centre deposition numbers for 8, 13, and 14: CCDC
1935838, 1935839, and 1935840. The data can be obtained free from Cambridge
Crystallographic Data Centre via https://www.ccdc.cam.ac.uk/structures/
Acknowledgment. LPB, AKG, DMS, and RPM acknowledge support from the National
Institutes of Health (SC1GM111158). EMG acknowledges support from the donors of the
Petroleum Research Fund of the American Chemical Society. AG acknowledges support
from the National Science Foundation (CHE-1856765). This work used Comet, the
Extreme Science and Engineering Discovery Environment (XSEDE) cluster at the San
Diego Supercomputer Center, which is supported by National Science Foundation grant
number ACI-1548562 through allocation CHE-180060. We also thank PSC-CUNY for
funding.
1
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Supplementary Data. H and C NMR spectra of all new compounds, a discussion on
characterization of 15d as a mixture, including 1H and 13C NMR data of PTAD (16d) and
dimer 8, graphs used to determine kinetic rate data, DFT computed data, and X-ray data
for 8, 13, and 14. This material is available free of charge via the Internet at
http://pubs.acs.org.
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