Intramolecular Vinylation of Aryl Rings by Vinyl Cations

Article abstract of DOI:10.1021/acs.orglett.8b03054

A Lewis acid mediated intramolecular electrophilic vinylation of aryl rings by vinyl cations is reported. This reaction takes advantage of β-hydroxy-α-diazo ketones as vinyl cation precursors and provides good yields of tricyclic 1-indenones that contain

Full text of DOI:10.1021/acs.orglett.8b03054

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Intramolecular Vinylation of Aryl Rings by Vinyl Cations
Jian Fang and Matthias Brewer*
Department of Chemistry, The University of Vermont, Burlington, Vermont 05405, United States
S
* Supporting Information
ABSTRACT: A Lewis acid mediated intramolecular electrophilic
vinylation of aryl rings by vinyl cations is reported. This reaction
takes advantage of β-hydroxy-α-diazo ketones as vinyl cation
precursors and provides good yields of tricyclic 1-indenones that
contain a seven-membered ring. Extending the alkane chain that
tethers the vinyl cation to the aromatic ring leads to 2-napthol and 2-
indenone products.
Scheme 1. Use of β-Hydroxy-α-diazo Ketone in a C−H
lectrophilic aromatic substitution is one of the most
Eimportant and frequently used methods for preparing
functionalized aromatic rings.1 A wide variety of strong
electrophiles can be used in these reactions with carbon-
based electrophiles giving the well-known Friedel−Crafts
reactions2 that were first reported over 140 years ago and
are still frequently used.3 While trisubstituted cations are
common electrophiles in Friedel−Crafts reactions, vinyl
cations, which would lead to styrenyl products, have not
received the same attention from the synthetic community.
Historically, this has been due to the fact that vinyl cations are
more difficult to prepare then their trisubstituted counterparts.
Adding electrophiles to alkynes is a useful method to prepare
vinyl cations, but although examples of applying this tactic in
Friedel−Crafts sequences exist,4 this approach suffers from
regioselectivity issues, and the initial styrenyl products can
react further to give polyaromatic alkanes.5 Metal catalyzed
hydroarylations and carboarylations have been developed to
mitigate these selectivity issues, but these approaches are
generally limited to acyclic alkynes, or large rings that are able
to accommodate the linear alkyne motif.6 Heterolysis of vinyl
triflates and related perfluorosulfonate esters provides an
alternative route to vinyl cations.7 However, these reactions
tend to be more facile in polar protic solvents, which lead to
the formation of solvolysis products. Nevertheless, Stang and
Anderson have reported that several vinyl triflates, including a
few cyclic examples, react at high temperature in aromatic
solvents to give styrenyl products, and they provide compelling
evidence for the intermediacy of vinyl cations in these
reactions.8 Nelson and co-workers recently reported a milder
variant of this reaction in which the vinyl triflate leaving group
is activated with a silylium ion.9 In this case, the silane also acts
as a reductant leading to aryl-alkane rather than styrenyl
products.
Insertion Reaction
nitrogen to give vinyl cation 3. The cation, which is
destabilized by the inductively withdrawing carbonyl, would
undergo a 1,2-shift across the alkene to give the ring expanded
cyclic vinyl cation 4.12 Remote C−H insertion of the vinyl
cation into a nonactivated pendent methyl C−H bond would
provide tertiary cation 5, and subsequent loss of a proton
would give the cyclopentenone product (6). In an effort to
further expand the use of vinyl cations in synthesis, we have
been exploring alternative intramolecular reactions that take
advantage of vinyl cations derived from β-hydroxy-α-diazo
carbonyls. In this paper, we describe our studies on the
intramolecular electrophilic vinylation of aryl rings by vinyl
cations that lead to tricyclic indenone products. Indenone and
indanone derivatives are important motifs that are present in a
number of biologically active compounds.13
We initiated these studies by preparing β-hydroxy-α-diazo
ketone 7 (Scheme 2) via the aldol-type addition of lithiated
diazoacetophenone to cyclohexanone. Treating diazo 7 with 1
equiv of SnCl4 in CH2Cl2 at room temperature returned
indenone 12 in 45% yield. This reaction presumably occurs by
the mechanism shown in Scheme 2. The Lewis acid would
facilitate elimination of the β-hydroxyl to generate vinyl
We have recently reported that β-hydroxy-α-diazo ketones
react with Lewis acids to generate cyclopentenone products via
the C−H insertion of a vinyl cation intermediate.10,11 We
propose that this transformation occurs by the sequence shown
in Scheme 1. Lewis acid mediated elimination of the tertiary
hydroxide would give vinyl diazonium ion 2, which would lose
Received: September 24, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b03054
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Letter
cyclohexanone. Methyl (14) and methoxy (16) substituents at
the para position returned indenones 15 and 17 in 72% and
68% yields respectively, while incorporating a chlorine at the
para-position (18) gave indenone 19 in 77% yield. This trend
is surprising at first glance since the electron-releasing groups
should increase the nucleophilicity of the aromatic ring and
promote the EAS reaction with the vinyl cation. However, a
more electron-rich aryl ring would also make the carbonyl
group less electron-withdrawing, and thus the initially formed
vinyl cation (e.g., 9, Scheme 2) should be more stable and less
prone to rearranging to the EAS precursor (e.g., 10). If the
initially formed vinyl cation has a longer lifetime, then it may
engage in undesired reactions. In this case, we observed some
product derived from trapping the initially formed vinyl cation
with a pentafluorophenyl group, which is presumably trans-
ferred from the hydroxy(triaryl)borate derivative of the Lewis
acid.
Positioning the chlorine substituent ortho to the ketone
(20) resulted in a substantial decrease in indenone yield
(32%), which may be due to the fact that there is one fewer
reactive site available on the aryl ring, resulting in a slower ring
closure and an increase in undesired side reactions.
Incorporating a strongly electron-withdrawing nitro group on
the aryl ring inhibited the reaction substantially; diazo 22
returned indenone 23 in only 8% yield. In view of the low
reactivity of nitro aryls in Friedel−Crafts reactions, and the fact
that this aryl ring is doubly deactivated, it is surprising that this
reaction returned any product.14 Including a methyl sub-
stituent meta to the carbonyl leads to the formation of two
regioisomeric indenones (25 and 26; Scheme 5) in a 1.5 to 1
ratio in 82% yield. Not surprisingly, the major product in this
case results from a reaction at the less sterically hindered
position of the aromatic ring.
Scheme 2. Indenone Formation via Aromatic Vinylation of a
Vinyl Cation
diazonium 8, which would lose molecular nitrogen to give
linear vinyl cation 9. This destabilized cation would rearrange
to give ring expanded cyclic vinyl cation 10,12 which would
react via intramolecular electrophilic aromatic substitution to
give indenone 12.
In our prior vinyl cation studies,10 we observed that
changing the Lewis acid can have a dramatic effect on the
efficiency of the reaction. With that in mind, we screened
several Lewis acids to see how they affected the reaction yield.
Aluminum trichloride, aluminum triflate, and scandium triflate
were each competent Lewis acids, but provided the product in
decreased yields (24%, 26%, and 60%, respectively). Treating
diazo 7 with trifluoroacetic acid did not give any desired
product, but instead returned 2-benzoylcycloheptan-1-one
(13) in 74% yield (Scheme 3). The Lewis acid of choice for
Scheme 3. TFA Mediated Ring Expansion
Scheme 5. Meta Substitution Leads to a Mixture of
Regioisomers
facilitating C−H insertion was tris-pentafluorophenyl borane
(BCF), which does not have a ligand that can easily trap the
cationic intermediates. We were pleased to find that treating
diazo 7 with BCF returned indenone 12 in 80% yield at room
temperature (Scheme 4). Adding MgSO4 to the reaction
mixture did not further improve the outcome.
With better defined reaction conditions in hand, we were
interested to see how substituents on the aromatic ring would
affect the outcome of the reaction. To this end, we prepared
the β-hydroxy-α-diazo carbonyls shown in Scheme 4 by the
addition of aryl-substituted diazoacetophenone derivatives to
To determine how modifications to the cycloalkane portion
of the molecule affect the reaction, we prepared the gem-
dimethyl (27) and tert-butyl (29 and 31) cyclohexane analogs
of 7 (Scheme 6), as well as cyclopentane derivative 32
(Scheme 7). The gem-dimethyl species (27) reacted smoothly
with BCF to give indenone 28 in 75% yield. Aldol addition of
lithiated diazoacetophenone to 4-tert-butylcyclohexanone gave
two diastereomeric addition products. These diastereomers
(29 and 31) were separable by column chromatography, and
Scheme 4. Inden-1-one Formation by Intramolecular
Vinylation of Aryl Rings
Scheme 6. Effect of Substitution on Aliphatic Ring
B
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the 4-methoxyaryl derivative (40, Scheme 9) reacted to give
indene-2-one 41 in 39% yield along with spiro[4.5]decane 42
Scheme 7. Formation of 1,2,3,4-Tetrahydro-9H-fluoren-9-
one
Scheme 9. Spirocycle Formation
each diastereomer was subjected to the Lewis acid reaction
conditions. In this case, the relative stereochemistry of the
diazo alcohol had no influence on the reaction outcome, and
both diastereomers gave the expected product (30) in
comparable yield. Changing the cyclohexane ring to a
cyclopentane had a dramatic negative effect on the product
yield. Diazo 32 reacted under the standard conditions to give
1,2,3,4-tetrahydro-9H-fluoren-9-one (33) as a mixture with a
chloro-trapped product. In this case, the chloride must be
transferred from the dichloromethane solvent. Switching to
dichloroethane prevented the formation of the unwanted side
product, but still returned fluorenone (33) in only 14% yield.
This low yield is a reflection of the instability of cyclohexenyl
cations due to the strain associated with constraining the vinyl
cation into a six-membered ring.15 The rearrangement of the
initially formed linear cation to the endocyclic vinyl cation is
less favorable, which results in diminished product yield.
To assess whether this reaction sequence could be used to
prepare other ring systems, we prepared diazo ketone 34
(Scheme 8), which includes an additional methylene unit
in 38% yield. The formation of the spirocycle is consistent with
Haack and Beck’s results on the Friedel−Craft’s acylation of
terminal alkynes with methoxyphenylacetyl chloride.17
In conclusion, reacting β-hydroxy-α-diazo ketones with
Lewis acids is a convenient method to form vinyl cations
that can engage in intramolecular electrophilic aromatic
substitution reactions. Depending on the length of the tether
connecting the aryl ring to the cation, 1-indenone, 2-indenone,
or 2-napthol products are formed in moderate to high yields.
While a strongly deactivating nitro group inhibited the
electrophilic aromatic substitution, this reaction tolerates
electron-rich and moderately electron-poor aryl rings. Overall,
this process offers a unique way to prepare indenones and
further highlights the utility of vinyl cations in synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 8. Change in Tether Length Provides 2-Napthol
Product
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03054.
General experimental details, experimental procedures,
1
compound characterization data, and copies of H and
13C NMR spectra (PDF)
AUTHOR INFORMATION
■
between the aryl ring and the carbonyl. In this case, the initially
formed cyclohexanone product would be expected to
tautomerize to give a 3,4-disubstituted 2-napthol derivative.16
In the event, treating diazo 34 with BCF at room temperature
gave cycloheptane substituted 2-napthol 35 in 42% yield. In
addition, indene-2-one 36 was recovered in 35% yield. This
latter product undoubtedly stems from reaction of the aryl ring
with the initially formed vinyl cation. Lowering the reaction
temperature led to diminished yields of both products, and
changing the Lewis acid to SnCl4 or AlCl3 gave little to no
desired reaction. The best outcome was achieved by treating
diazo 34 with 1 equiv of BCF at room temperature in the
presence of 1 equiv of MgSO4. In this case, 2-napthol 35 was
recovered in 47% yield, with an additional 21% yield of indene-
2-one 36. We thought it might be possible to minimize the
formation of the indene-2-one side product by decreasing the
nucleophilicity of the aryl ring, thus slowing the rate of the ring
closure onto the initially formed vinyl cation. To this end, we
prepared the 4-chloroaryl derivative 37 and subjected it to the
optimized reaction conditions. In this case, the corresponding
indene-2-one was not formed, but the yield of the desired 2-
napthol (38) did not improve.
Corresponding Author
*E-mail: Matthias.brewer@uvm.edu.
ORCID
Matthias Brewer: 0000-0003-4250-7195
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the NSF (Award
Number CHE-1665113). Mass spectrometry data were
acquired by Bruce O’Rourke on instruments purchased
through instrumentation grants provided by the National
Institutes of Health (NIH) (S10 OD018126).
REFERENCES
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