Synthesis of aryl-substituted 2-methoxyphenol derivatives from maltol-derived oxidopyrylium cycloadducts through an acid-mediated ring contraction cascade

Article abstract of DOI:10.1039/c9cc09213g

Oxidopyrylium cycloadducts derived from maltol and aryl acetylenes undergo acid-mediated rearrangements to generate aryl-substituted 2-methoxyphenol (guaiacol) derivatives. Specifically, the cycloadducts react with boron trichloride to form 2-methoxy-5-ar

Full text of DOI:10.1039/c9cc09213g

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Synthesis of Aryl-Substituted 2-Methoxyphenol Derivatives from
Maltol-Derived Oxidopyrylium Cycloadducts through an Acid-
Mediated Ring Contraction Cascade
Received 00th January 20xx,
Accepted 00th January 20xx
Lauren P. Bejcek,a,b Ryan P. Murelli‡a,b,c
DOI: 10.1039/x0xx00000x
Oxidopyrylium cycloadducts derived from maltol and aryl developing and exploiting intermolecular 3-hydroxy-4-pyrone-
4
acetylenes undergo acid-mediated rearrangements to generate based cycloadditions. To date, our lab has found particular
5
aryl-substituted
2-methoxyphenol
(guaiacol)
derivatives. interest in both boron trichloride and sulfonic acid-mediated
6
Specifically, the cycloadducts react with boron trichloride to form rearrangements
of
allomaltol-derived
oxidopyrylium
2-methoxy-5-arylphenol molecules, and with methane sulfonate cycloadducts. In some instances, the choice of acid can have a
to form 2-methoxy-4-aryl-6-methylphenol molecules.
dramatic difference on product outcome, highlighted by the
rearrangement of dimethyl acetylene dicarboxylate
2
-methoxyphenol (or guaiacol) is a naturally occurring benzene
cycloadducts
(
1
to either furan
2
or 7-hydroxytropolones
Scheme 1A). We have recently presented studies detailing
oxidopyrylium cycloadditions with maltol-derived
3
1
derivative found in both the parent form, and also embedded
in countless natural products and biologically active synthetic
constructs. Among them are various aryl-substituted guaiacol
5,6
2
7
oxidopyrylium ylides, and became interested in exploring
acid-mediated ring-opening reactions on these cycloadducts.
Our hypothesis was that the alternative positioning of the
methyl group might lead to an alternative ring-opening to form
derivatives that have demonstrated a variety of different
biological activities, particularly against cancer cells (Figure 1).3
Thus, new approaches towards aryl-substituted guaiacol
derivatives would be valuable in both medicinal chemistry and
total synthesis efforts. The present manuscript describes our
discovery that oxidopyrylium cycloadducts derived from maltol
and aryl acetylenes react with boron trichloride and methane
sulfonic acid to generate aryl-substituted guaiacol derivatives.
8
4
-hydroxytropolones (ie 7, Scheme 1B). Instead, when
phenylacetylene-derived cycloadduct 4a was treated to boron
trichloride, the known molecule 2-methoxy-5 phenylphenol
9
5
a was generated in 71% yield.
Figure 1. Examples of anti-cancer natural products and
synthetic constructs possessing guaiacol-aryl appendages.
This discovery emerged from our lab’s ongoing interest in
a.Department of Chemistry, Brooklyn College, The City University of New York,
Brooklyn, NY, USA
PhD Program in Chemistry, The Graduate Center, The City University of New York,
b.
Scheme 1. Acid-mediated reactions of oxidopyrylium-alkyne
cycloadducts. (A) Example of previously established acid-
New York, NY, USA
c.
PhD Program in Biochemistry, The Graduate Center, The City University of New
mediated ring-openings of an allomaltol-derived cycloadduct
to furan or 7-hydroxytropolone . (B). Anticipated outcome
for acid-mediated ring-opening of maltol-derived cycloadduct
4a ), and observed guaiacol product 5a
1
York, NY, USA
†
Footnotes relating to the title and/or authors should appear here.
2
3
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
(

7
.
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Journal Name
o
Our current hypothesis is that the ring-opening takes place 120 C in a microwave, this yield could be increased to 90%
View Article Online
DOI: 10.1039/C9CC09213G
toward rather than away from the methyl group, resulting in
the secondary carbocation (
opening takes place, the molecule can undergo a ring- yields ranging from 52-80% (11/12
contraction ( ) and then aromatize via a reverse-Friedel- Gratifyingly, these cycloadducts, which included electron-poor,
Crafts acylation. It is unclear if the acylium ion is formed, as rich, sterically demanding, and heteroaromatic, were all
when the reaction was monitored in CDCl , we only observed capable of proceeding to the corresponding 2-methoxyphenol
acetyl chloride, and no acetophenone was observed when the derivatives (4a-g 5a-g), in yields ranging from 50-75%. We
reaction was performed with benzene as co-solvent. Thus, it is also carried out the cycloaddition with methyl-ketone
possible that the chloride ion assists in the deacylation. While derivative 14 Scheme 2B). In this instance, the reaction yield
(
11/12

4a, Scheme 2).
We also carried out the
8
,
Scheme 1B). Once the ring- cycloaddition with six alternative arylacetylenes and achieved
4b-e Scheme 2A).

,
8
 9
1
0
3

(
the regioselectivity of the ring-opening was not anticipated, was low and further complicated by the production of two
particularly in light of the high carbocation stabilization on ring-contraction products, 15 and 16, the latter of which would
account of the phenyl group (ie, 6), we speculated that this arise through tautomerization-based rearomatization rather
could be explained electronically based upon a combination of than deacylation. It is possible that the methyl ketone in this
the carbonyl destabilizing the cation of the anticipated instance serves as an internal base to facilitate the
regioisomeric ring-opening intermediate (
resonance stabilization of the presumed carbocation through
the α-methoxyenone ( Scheme 1).
6
), as well as tautomerization, leading to substantial production of 16
.
8
,
During the course of these studies, we also found that
sulfonic acids were capable of promoting formation to
alternative 2-methoxyphenol derivatives, 19a-g (Scheme 3). In
this instance, methane sulfonic acid provided the highest
yields, which were only 41% in the best case. Slightly lower
yields were observed with triflic acid, and comparable yields
were obtained when boron trifluoride diethyl etherate was
used (result not shown). Consistent with the proximity of the
appendage to the resultant carbocation, the reaction did not
work with the more electronically poor aromatic acetylene
derivative 4d or methyl ketone-derived bicycle 14 (result not
shown). In addition, the more sterically-charged napthyl-
derived bicycle 4g was also low yielding, which could be on
account of the steric nature of the tertiary carbon atom that
results from the ring-contraction (see 18). We believe this
transformation proceeds through a mechanistically analogous,
albeit
regioisomerically
different,
ring-opening/ring-
contraction/retro-Friedel Crafts cascade process, to that
previously proposed with boron trichloride.
Scheme 2. Substrate scope for oxidopyrylium cycloaddition
route to guaiacol derivatives. Synthesis of (A) aryl acetylene-
derived and (B) 3-butyn-2-one-derived cycloadducts, and
products resulting after reaction with boron trichloride.
Given both the high yields and value of the
2
-methoxyphenol, we felt this unanticipated reaction was
worth exploring further. Our first task was to optimize the Scheme 3. Ring-contraction of oxidopyrylium cycloadducts
cycloaddition, as we had previously carried out the reaction to mediated by methane sulfonic acid, along with mechanistic
characterize new molecules for mechanistic purposes, and hypothesis.
7
achieved only 16% yield. After optimization, we found that by
performing the cycloaddition using purified maltol-derived
The combination of these results provide interesting
dimers (11 and 12) and phenylacetylene as the solvent at insight related to acid-mediated oxabicycle ring-openings and
2
| J. Name., 2012, 00, 1-3
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rearrangements more generally that are worth discussing.
Firstly, given the alternative regioisomeric opening of methane
sulfonic acid suggests that boron trichloride-mediated ring-
opening may be more likely driven by coordination rather than
carbocation stabilization, although reversibility of the ring-
opening may also be at play, and the difference could be
driven by downstream preferences. Either way, these results
provide precedence for chemical control over the
regioselectivity of the ring-opening of oxidopyrylium
cycloadducts. Furthermore, in one of our early studies we
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DOI: 10.1039/C9CC09213G
reported that regioisomeric cycloadduct 20 reacts with triflic
6
acid very cleanly to form tropolone 23
(
Scheme 4A). Given
both the electronic similarities between proposed
intermediates 21 and , as well as the presence of an even Scheme 4. Acid-mediated rearrangments of oxidopyrylium
weaker conjugate base than was used in the formation 19a
8
,
cycloadducts to tropolones. (A) Triflic acid-mediated ring-
6
there must be some structural preference for 21 to undergo opening of cycloadducts 16, which is an isomer of 4a. (B)
the elimination. One possibility is that it proceeds through an Boron trifluoride-mediated ring-openings of benzo-fused
11
internal acid-base process facilitated by the proximity of the oxidopyrylium cycloadducts 24
carbonyl (similar to proposal for formation of 16), which could
.
result in the clean formation of product. Similar high yields
were observed by Friedrichsen in his seminal studies on ring-
openings of oxidopyrylium cycloadducts (Scheme 4B).11
Conclusions
In conclusion, oxidopyrylium cycloadducts derived from maltol
and aryl acetylenes can undergo an acid-promoted ring-
contraction/aromatization cascade process to form aryl-
substituted guaiacol derivatives. Given the broad interest in
Mechanistic studies are warranted to gauge these differences
in an effort to predict and control the product formation in
acid-mediated ring-opening reactions of oxidopyrylium
cycloadducts.
12
developing oxidopyrylium cycloaddition reaction and using
13
this reaction in complex target synthesis, these studies
represent a new utility for oxidopyrylium cycloadducts that
could find usage in natural product synthesis and medicinal
chemistry-based pursuits. They furthermore provide valuable
information on the propensity of oxidopyrylium cycloadducts
to undergo acid-mediated rearrangements.
Conflicts of interest
There are no conflicts to declare.
Notes and references
‡
1
2
Corresponding author email: rpmurelli@brooklyn.cuny.edu
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