Selective Mono-allylation of 1,3-Diketones and Their Use in the Synthesis of 3-Allyl Chromones and Benzannulated 6,5-Bicyclic Ketals

Article abstract of DOI:10.1002/asia.201801695

The selective mono-allylation of 1,3-diketone containing compounds is described. The reaction proceeds under mild reaction conditions and in moderate to high yield (66–99 %). Using this procedure to access the key mono-allylated intermediate, the hitherto difficult to access 3-allyl chromones were synthesized in excellent yield (87–98 %). Finally, the utility of this newly developed procedure was showcased through the rapid synthesis of the scaffold of the xyloketal family of natural products.

Full text of DOI:10.1002/asia.201801695

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Accepted Article
Title: Selective mono-allylation of 1,3-diketones and their use in the
synthesis of 3-allyl chromones and benzannulated 6,5-bicyclic
ketals
Authors: Brooke Swaney, Sinan Gai, Mitchell Clark, and Bill C.
Hawkins
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To be cited as: Chem. Asian J. 10.1002/asia.201801695
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10.1002/asia.201801695
Chemistry - An Asian Journal
COMMUNICATION
Selective mono-allylation of 1,3-diketones and their use in the
synthesis of 3-allyl chromones and benzannulated 6,5-bicyclic
ketals
Brooke E. Swaney, Sinan Gai, Mitchell R. Clark and Bill C. Hawkins*[a]
Abstract: The selective mono-allylation of 1,3-diketone containing
compounds is described. The reaction proceeds under mild reaction
conditions and in moderate to high yield (66-99%). Using this
procedure to access the key mono-allylated intermediate, the hitherto
difficult to access, 3-allyl chromones were synthesized in excellent
yield (87-98%). Finally, the utility of this newly developed procedure
was show cased through the rapid synthesis of the scaffold of the
xyloketal family of natural products.
Mono-alkylation of doubly activated beta-diketones has
historically been problematic, with the mono-alkylated product
sometimes being more nucleophilic than the starting diketone. In
addition, C- vs O-alkylation, retro-Claisen reactions, and the
instability of alkylating agents to basic media, are all issues
encountered and can give rise to a mixture of products.1 The use
of beta-diketones in the form of their cobalt(II) complexes has
extended the scope of their C-alkylations and allylations.2
Oxidative additions of 1,3-dicarbonyl compounds to alkenes can
be initiated using one-electron oxidizing agents such as ceric
ammonium nitrate (CAN)3 and manganese (III) acetate,4 however
these reactions often result in the production of dihydrofurans or
nitrate esters. Allylations can be further improved by using silicon
as a beta-carboradical stabilizer,5 however this limits the user to
specific reagents. Transition metal mediated allylations are
uniquely placed to provide access to the mono-allylated species.6
Notably, transition metal mediated intermolecular mono-allylation
of 1,3-diketones has been the subject of several studies.7
Scheme 1. Synthetic strategy to access mono-allylated 1,3-dicarbonyl
compounds.
In order to validate our approach we prepared the known 1,3-
diketone 1a.10 Pleasingly, treatment of compound 1a with
Pd(PPh3)4 (10 mol%) and potassium carbonate in methanol at
room temperature afforded the 2-allyl-1,3-diketone 3a in a 91%
yield after 40 minutes (Scheme 2A). In comparison, we treated
the phenol 4 with 2.2 equivalents of allyl bromide in the presence
of potassium carbonate in DMF (Scheme 2B).11 This provided the
2,2-diallylated compound 5a in 22% yield along with the mono-2-
allylated analog 5b in a 40% yield, which was difficult to isolate
and required several chromatographic purifications. Conversely,
treatment of the allyl ether 1a with one equivalent of allyl bromide
provided the 2,2-diallylated compound 5a in a 46% yield (Scheme
2C). These experiments clearly demonstrate the difficulty in
cleanly obtaining mono-2-allylated analogs under standard
reaction conditions.
The Tsuji-Trost allylation reaction has been known for over 50
years, and has been the focus of intense research leading to
numerous modified procedures.8 Intramolecular asymmetric allyl-
transfer reactions have received significant attention including
elegant work describing enantioconvergent decarboxylative
allylations.9 Given the reliability of this reaction class we were
surprised to find no reports of its use in the context of
intramolecular allyl-transfer to the 2-position of a 1,3-diketone.
Herein, we report a reliable, efficient and scalable synthetic route
to 2-allyl-1,3-dicarbonyl compounds of the general structure 3
(Scheme 1). The utility of this reaction was then demonstrated
through construction of various chromones and xyloketal-like
natural product scaffolds.
[a]
Ms B. E. Swaney, Ms S. Gai, Mr M. R. Clark, Dr. B. C. Hawkins
Department of Chemistry
University of Otago
Dunedin 9054
E-mail: bhawkins@chemistry.otago.ac.nz
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/asia.201801695
Chemistry - An Asian Journal
COMMUNICATION
Scheme 2. Synthetic strategies for mono-allylation of 1,3 diketones. *yield
based on starting 1,3-diketone as limiting reagent.
failed to undergo any reaction, despite elevated reaction
temperature, with starting material being returned.
The generality and scope of the reaction were then examined as
illustrated in Scheme 3. Systematic variation of the eastern
portion of the 1,3-diketone was first investigated, both alkyl (3b),
heteroaromatic (3c) and electron rich aromatic (3d), unsubstituted
aromatic (3a) and electron withdrawing aromatic (3e) functional
groups were well tolerated. Notably, aromatic rings containing the
strongly electron withdrawing nitro group resulted in mixtures of
the expected product along with the corresponding flavone (vide
infra).
Scheme 4. Examination of reactivity for crotyl and prenyl derivatives.
With a clear picture of substrate scope established we next sought
to utilise the procedure in the context of a high value target.
Previous work has shown 3-allyl chromones to be a privileged
structure for drug discovery.12 Current methods to make 3-allyl
chromones include Stille type cross-couplings with allyl
tributyltin,13 gold mediated intramolecular cyclization of aryl ethers
to ynones,14 and most recently they have been accessed via a
tandem Michael addition- Claisen rearrangement-O-arylation.15
Limitations to these methods include the use of highly toxic tin
reagents, expensive gold catalysts, plus high reaction
temperatures and long reaction times. In addition to this, the
scope of substituents has been focussed on flavone derivatives
with only a limited number of 3-allyl chromones described. The
absence of an efficient protocol with good substrate tolerance,
highly accessible reagents, and high yields has limited the further
study on 3-allyl chromones. Therefore, a complementary method
which can provide access to this structure type, under mild
reaction conditions and in high yield, would be of significant value.
With this in mind, treatment of allyl ether 1a with Pd(PPh3)4 and
potassium carbonate in methanol at room temperature for 40 mins,
followed by the addition of aqueous 1M HCl, smoothly provided
the corresponding chromone 9a in a 94% yield (Scheme 5). The
flavone 9b was formed rapidly with only small amounts of the
intermediate 2-allyl-1,3-diketone observed (1H NMR) after 20
mins. Complete conversion to the flavone 9b occurred after 30
mins which was then isolated in an 87% yield. Chromones 9c-e
could all be isolated in high yield following the treatment with acid
(conditions A, Scheme 5). Conversely for the relative electron rich
systems, the crude reaction mixture containing the 2-allyl-1,3-
diketone intermediate required harsher reaction conditions in
order to undergo dehydration (conditions B, Scheme 5,
compounds 9f-9h).
Scheme 3. Substrate scope for the mono-allylation of 1,3-diketones
This was followed by variation of the western portion of the 1,3-
dicarbonyl motif. Aryl bromides (3f, 3g and 3m) were readily
accessed under the standard reaction conditions in good yield.
Furthermore, these structures also provide a handle for further
Palladium mediated functionalization. The relatively electron rich
aryl systems derived from 5-methyl-2-hydroxyacetophenone and
4-methoxy-2hydroxyacetophenone furnished the corresponding
mono-allylated compounds in good to excellent yields (3h-3l).
Notably, attempts to extend the methodology to acetophenone
derivatives and benzyl 1,3-diketones were unsuccessful with
unidentifiable complex mixtures formed under the established
reaction conditions.11 Furthermore, the crotyl based system 6 was
found to provide a 3:1 mixture of the linear and branched alkenes
7a and 7b, respectively (Scheme 4). Whilst the prenyl ether 8
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Chemistry - An Asian Journal
COMMUNICATION
ethers 11a-e with Pd(0) and potassium carbonate in methanol at
room temperature for 1h, provided the corresponding
benzannulated 6,5-bicyclic acetal (14a-e) in good to excellent
yield.
Scheme 5. Synthesis of 3-allyl chromones
Inspired by the ease of chromone formation, we sought to further
extend the methodology. It was envisaged that the presumed
intermediate lactol anion 13 could act as a nucleophile and
undergo an oxa-Michael addition onto an appropriate -
unsaturated ester to afford a tetrahydrofuranobenzopyranone of
the general structure 14 (Scheme 6). This tricyclic ring system is
present in the xyloketal family of natural products which have
been suggested as lead compounds for the development drugs
for neurological disorders.16 Cognizant that the dehydration
pathway to form the chromone would be a competing pathway,
the corresponding methyl diketones 10a-e were prepared using a
modified literature procedure.17 Cross metathesis with methyl
acrylate in the presence of a catalytic amount of phenol18 provided
the precursor aryl ethers 11a-e (Scheme 6). Treatment of the aryl
Scheme 6. Rapid synthesis of the xyloketal scaffold
Notably, the shortening of the synthetic route via direct alkylation
of the phenol 16 with methyl 4-bromocrotonate under basic
conditions resulted in formation of the oxepine 17, rather than the
corresponding allylic ether (Scheme 7). In conclusion, we have
developed a selective method for the synthesis of mono-allylated
1,3-diketone compounds which was used to gain rapid and much
improved access to 3-allyl chromones. Furthermore, we
described an allyl migration/lactolisation/Oxa-Michael addition
domino reaction process which gave access to the xyloketal
natural product scaffold. This work is expected to facilitate further
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Tang, X. Zhang, H. -F. Tu, and S. -L. You, J. Am. Chem. Soc., 2018, 140,
7737.
study into this interesting building block. Efforts towards this aim
remain ongoing and will be reported in due course.
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[11] See Supporting Information for details
Scheme 7. O-alkylation followed by ring closure afford the benzo-oxepine 17.
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893.
[13] T. T. Dao, J. W. Oh, Y. S. Chi, H. P. Kim, K. S. Sin and H. Park, Arch.
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Keywords: chromone • synthetic methodology • xyloketal •
allylation • domino reactions
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Brooke E. Swaney, Sinan Gai, Mitchell
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Selective mono-allylation of 1,3-
diketones and their use in the
synthesis of 3-allyl chromones and
benzannulated 6,5-bicyclic ketals
A novel intramolecular Tsjui Trost allylation is described, the methodology is then
showcased through the construction of the xyloketal scaffold.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.