Dihalohydration of Alkynols: A Versatile Approach to Diverse Halogenated Molecules

Article abstract of DOI:10.1002/ejoc.201800668

In this paper we outline how dihalohydration reactions of propargylic alcohols can be used to access a wide variety of useful halogenated building blocks. A novel procedure for dibromohydration of alkynes has been developed, and a selection of dichloro and dibromo diols and cyclic ethers were synthesized. The dihalohydration of homo-propargylic alcohols provides a useful route to 3-halofurans, which were shown to readily undergo cycloaddition reactions under mild conditions. Finally, a novel ring expansion of propargylic alcohols containing a cyclopropylalkyne provides access to halogenated alkenylcyclobutanes.

Full text of DOI:10.1002/ejoc.201800668

A Journal of
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Title: Dihalohydration of Alkynols: A Versatile Approach to Diverse
Halogenated Molecules
Authors: Samantha M Gibson, Jarryl D'Oyley, Joe Higham, Kate
Sanders, Victor Laserna, Abil Aliev, and Tom David Sheppard
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10.1002/ejoc.201800668
European Journal of Organic Chemistry
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Dihalohydration of Alkynols: A Versatile Approach to Diverse
Halogenated Molecules
Samantha M. Gibson, Jarryl M. D’Oyley, Joe I. Higham, Kate Sanders, Victor Laserna, Abil E. Aliev
and Tom D. Sheppard*[a]
Dedication ((optional))
Abstract: In this paper we outline how dihalohydration reactions of
propargylic alcohols can be used to access a wide variety of useful
halogenated building blocks. A novel procedure for dibromohydration
of alkynes has been developed, and a selection of dichloro and
dibromo diols and cyclic ethers were synthesized. The
dihalohydration of homo-propargylic alcohols provides a useful route
to 3-halofurans, which were shown to readily undergo cycloaddition
reactions under mild conditions. Finally, a novel ring-expansion of
propargylic alcohols containing an alkynylcyclopropane provides
access to halogenated alkenylcyclobutanes.
dihaloketones from readily available precursors. To date,
however, the potentially interesting chemistry of these
functionalized dihalides has not been explored in great detail.
As part of our ongoing interest in the development of novel
chemistry employing propargylic alcohols,[11] we recently
reported two methods for the dihalohydration of these systems 1
(Scheme 1), with a gold-catalysed iodination reaction providing
access to previously unreported ,-diiodo--hydroxyketones 2,
and a catalyst-free procedure using trichloroisocyanuric acid
(TCIA) giving ,-dichloro--hydroxyketones 3. The latter
procedure could also be extended to alkynols 4 giving access to
dichlorolactols of general structure 5a or 5b.
Introduction
Halogenated molecules play an important role in organic
chemistry, both as synthetic targets themselves, and as useful
reactants for a wide range of metal-catalysed reactions. For
example, chlorinated and brominated functional groups are
widely present in agrochemicals[1] and in flame retardants,
although the latter are causing increasing environmental
concerns.[2] They are also widely used starting materials for a
range of organometallic cross-coupling methodologies.[3]
Geminal dihalides have found application as carbene or
carbenoid precursors which undergo reaction with metals (e.g.
Zn), metal salts (e.g. CrCl2), or organometallic reagents (e.g.
Et2Zn) to initiate cyclopropanation or olefination reactions.[4]
Dihaloketones can also serve as useful precursors to enolates
under reducing conditions.[5] The synthesis of functionalized
geminal dihalides is rare, however, as most halogenation
processes require harsh conditions. For example, geminal
dihalides can be generated from carbonyl groups using
deoxohalogenation reagents such as PCl5, or via halogenation
of the hydrazine or oxime derivatives.[6] Alternative methods via
double carbometallation of alkynes are also incompatible with
functionalized substrates.[7] We,[8] and others,[9-10] have observed
that dihalohydration of alkynes offers a mild and preparatively
useful approach to ,-dihaloketones. These reactions usually
proceed with high regioselectivity, and provide functionalized
Scheme 1. Previous work on the diiodohydration and dichlorohydration of
alkynols.[8]
In this article, we describe the extension of this work to the
dibromohydration of alkynols, and we also describe preliminary
studies on the application of geminal dibromides and dichlorides
in further synthetic transformations to access a diverse range of
potentially useful halogenated molecules, many of which
constitute previously unreported structural frameworks.
Results and Discussion
[a]
Dr S. M. Gibson, Dr J. M. D’Oyley, Ms K. Sanders, Mr. J. I. Higham,
Dr V. Laserna, Dr A. E. Aliev, Dr T. D. Sheppard
Department of Chemistry
We set out to develop a method to convert readily accessible
University College London
propargylic
alcohols
into
the
corresponding
Christopher Ingold Laboratories, 20 Gordon St, London, WC1H 0AJ,
U.K.
E-mail: tom.sheppard@ucl.ac.uk
dibromohydroxyketones, whose properties remain relatively
unexplored,[10] although they have recently been demonstrated
as effective bioisosteres for hydrated ketones in quorum-sensing
inhibitors.[12] The required dibromohydration of propargylic
alcohols was achieved efficiently using dibromoisocyanuric acid
Homepage: www.tomsheppard.eu
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/ejoc.201800668
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(DBIA)[13] under closely related conditions to our previously
described dichlorohydration reaction.[8] Our initial experiments
suggested that the reaction was more efficient with a higher
proportion of water in the reaction medium (30% rather than
10% H2O in MeCN).
pyridine heterocycle (6k). A very electron-deficient benzene ring
(6l) led to a low yield of the desired dibromide, however. Both
aryl and alkyl chains could be incorporated as the R2 substituent,
including some functional groups (ester 6d, aryl bromide 6e-6f).
The novel dichlorides 7n and 7o were also prepared using our
previously reported dichlorohydration method. Interestingly, the
dibromohydration of an ethoxyacetylene 1p led to the formation
of both the desired dibromide 6p and the monobrominated
compound 8. The formation of this latter compound as a single
diastereoisomer is consistent with our proposed mechanism in
which the halogenation reaction proceeds via formation of
heterocycle 9 through incorporation of a molecule of acetonitrile
(Scheme 3). Heterocycle
9 can then undergo a second
bromination to give dibromide 10 which then hydrolyses to yield
the dibromoketone product 6. Alternatively, protonation of highly
electron rich heterocycle 9 (where R1=OEt) may take place
selectively on the least hindered side to give 11 which will yield
syn-bromohydrin 8 as the major diastereoisomer after hydrolysis.
Scheme 3. Proposed mechanism for dibromohydration
Scheme 2. Dibromohydration of propargylic alcohols.
Pleasingly, the reaction could be applied to primary,
secondary and tertiary propargylic alcohols (Scheme 2, e.g. 6a,
6b, 6c). As noted previously, an aryl group on the alkyne was
necessary for efficient reaction. However, unsubstituted phenyl
rings (6a, 6b, 6e, 6n) and both electron rich (6c, 6d, 6g, 6h, 6j,
6m) and electron deficient (6l, 6m) aryl groups could be used,
including examples bearing polyaromatic rings (6i) and a
Scheme 4. Dibromohydration and dichlorohydration of extended alkynols.
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10.1002/ejoc.201800668
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The bromination reaction could be extended to the
synthesis of dibromolactols 12a-12d through reaction of
extended alkynol derivatives (Scheme 4), including compounds
containing primary (12a, 12c), secondary (12d) and tertiary
(12b) alcohols. Dichlorides 13a and 13d were also prepared via
dichlorohydration of the alkynes using TCIA.
and 7o could readily be converted with high diastereoselectivity
into
the
anti-dichlorodiols
18
via
reduction
with
Me4NB(OAc)3H.[14] The same procedure was also used to
access anti-bromodiol 19. We next set out to investigate a
complementary method to access the corresponding syn-
dihalodiols. Reduction of 6g with DIBAL-H in the presence or
absence of ZnCl2[15] led to the formation of a mixture of products
including desired syn-diol 20, monobrominated anti-diol 21, and
brominated allylic alcohol 22, with the zinc chloride leading to an
enhanced selectivity in favor of the desired diol 20. An
alternative reduction protocol using catechol borane[16] gave a
mixture of syn and anti diols in 82% overall yield (82:18 dr), from
which the desired syn diol 20 could be isolated in 64% yield. The
stereochemistry of 20 was confirmed through formation of the
acetonide 23 which displayed an nOe between the two axial
protons
indicated.
Using
the
same
method,
dichlorohydroxyketone 7n was converted into the corresponding
syn-dichlorodiol 24 in 90% yield. Interestingly, dibromo-1,3-diols
such as 19 and 20 have never previously been synthesised.[17]
Scheme 6. Synthesis of 3-Halofurans
Scheme 5. Reduction of geminal dihalides to access halogenated diols and
cyclic ethers.
We envisaged that lactols such as 12a could readily be
converted into synthetically useful 3-halofurans[18] through formal
elimination of water and HX. Attempts to convert 12a directly
into the 3-bromofuran were unsuccessful. However, further
investigation determined that 3-halofurans could be successfully
obtained through conversion of the lactols 12a, 13a and 13d into
the mixed ketal derivatives 25a-25c with AcCl/MeOH, followed
by basic elimination of methanol and HX. Using this sequence,
With a selection of dihalohydroxyketones and dihalolactols
in hand, we examined their reduction to access halogenated
diols and cyclic ethers. Pleasingly, lactols 12a and 13a could be
converted into the corresponding dihalo-1,4-diols 14/15 or
dihalogenated tetrahydrofurans 16/17 through treatment with
NaBH4 or TFA/Et3SiH respectively. Dichlorohydroxyketones 7n
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10.1002/ejoc.201800668
European Journal of Organic Chemistry
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we were able to access 3-bromofuran 26a, 3-chlorofuran 26b
and trisubstituted bromofuran 26c; with complete control over
the substitution pattern in the latter compound. This approach is
b, e]
complementary to routes employing ynones,[18a,
providing
access to a different regioisomer of the 3-halofuran.
We have previously reported that 3-alkoxyfurans are
readily able to undergo Diels-Alder reaction with maleimides to
provide endo-cantharimide derivatives, which are promising
lead-like molecules for medicinal chemistry.[19] 3-Halofurans
have been reported to show enhanced reactivity in
intramolecular Diels-Alder reactions,[20-21] so we were therefore
interested in exploring their reactivity with maleimides to access
useful halogenated cantharimide derivatives. 3-Bromofuran 26c
gave the endo cantharimide 27 as a single diatereoisomer in
excellent yield upon reaction with N-methylmaleimide. However,
3-chlorofuran 26b gave a mixture of the separable endo and exo
cantharimides 28 in moderate overall yield under similar
conditions.
Scheme 8. Synthesis of cyclobutanes via ring-expansion of propargylic
alcohols containing cyclopropylacetylenes.
Conclusions
We have reported a new method for the dibromohydration of
alkynols to give dibromoketones that is applicable to a wide
range of substrates, along with the extension of our previously
reported dichlorohydration reaction to new substrates. The
dihaloketones obtained from these reactions can be used to
prepare structurally diverse halogenated molecules including
dihalodiols, dihalogenated tetrahydrofurans, 3-halofurans, and
halogenated cantharimides. We have also discovered a novel
halogenation/ring expansion of alkynylcyclopropanes which
provides alkenylcyclobutanes. Many of these classes of
halogenated compound have never previously been prepared.
Further work is underway to optimize these methods, and to
explore the interesting properties of these structurally unusual
molecules.
A
further interesting transformation was uncovered upon
attempted dibromination of cyclopropyl-containing propargylic
alcohol 1q, which yielded the vinylcyclobutane 29a as the major
product as a mixture of diastereoisomers. This reaction was
extended to the synthesis of 29b.[22] Although ring-expansion of
cyclopropanes to cyclobutanes is precedented,[23] the direct ring-
expansion of cyclopropylacetylenes has rarely been observed.
[24]
Experimental Section
Full experimental procedures for the preparation of all compounds, along
with 1H and 13C spectra for all novel compounds can be found in the
supporting information.
Acknowledgements
We would like to thank the UCL Department of Chemistry for
providing an EPSRC studentship to SMG, the UCL Drug
Discovery PhD Programme for providing an EPSRC studentship
to JMD, the Leverhulme Trust for providing PDRA funding for VL
(RPG-2017-221), and the EPSRC National Mass Spectrometry
Facilty at Swansea University for assistance with analysis of
some samples.
Keywords: Halogenation • Alkynes • Alcohols • Heterocycles •
Scheme 7. Cycloaddition reactions of 3-halofurans.
Ketones.
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Halogenated Molecules
Samantha M. Gibson, Jarryl M. D’Oyley,
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Dihalohydration of Alkynols: A
Versatile Approach to Diverse
Halogenated Molecules
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