Regiodivergent halogenation of vinylogous esters: One-pot, transition-metal-free access to differentiated haloresorcinols

Article abstract of DOI:10.1021/ol503561x

We report an efficient method for the regiodivergent synthesis of halogenated resorcinol derivatives using readily available vinylogous esters and sulfonyl halide halogen donors. Either the 4- or 6-haloresorcinol isomer is accessible from a common precursor. In contrast to conventional oxidants for arene halogenation, mild sulfonyl halides allow broad functional group compatibility. The strategy inherently differentiates the two resorcinol oxygen atoms and enhances the potential for complex molecule synthesis.

Full text of DOI:10.1021/ol503561x

Letter
pubs.acs.org/OrgLett
Regiodivergent Halogenation of Vinylogous Esters: One-Pot,
Transition-Metal-Free Access to Differentiated Haloresorcinols
Xiaohong Chen, Jenny S. Martinez, and Justin T. Mohr*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States
S
* Supporting Information
ABSTRACT: We report an efficient method for the regiodivergent synthesis of
halogenated resorcinol derivatives using readily available vinylogous esters and
sulfonyl halide halogen donors. Either the 4- or 6-haloresorcinol isomer is accessible
from a common precursor. In contrast to conventional oxidants for arene
halogenation, mild sulfonyl halides allow broad functional group compatibility.
The strategy inherently differentiates the two resorcinol oxygen atoms and enhances
the potential for complex molecule synthesis.
ubstituted aromatic systems are principal substructures in a
wide variety of important organic molecules including
Scheme 1. Naturally Occurring Bioactive Aryl Halides
S
bioactive natural products (Scheme 1), pharmaceuticals, agro-
chemicals, and polymers.1 The advent of efficient cross-coupling
protocols predicated on the availability of aryl halide feedstocks
has enhanced arene synthesis significantly.2 However, the
preparation of substituted haloarenes is not always straightfor-
ward. Classical electrophilic aromatic substitution reactions
between arenes and strong electrophiles such as elemental
halogens (Scheme 2a)3 are complicated by issues of regio-
selectivity and overhalogenation, particularly with electron-rich
aromatics,4 and much effort has been exerted to overcome these
limitations with transition-metal-catalyzed substitutions.5 Re-
cently, alternative strategies have accessed arenes via oxidation of
cyclohexenone derivatives.6 For instance, Stahl and co-workers
described Pd-catalyzed oxidation methods that transfer existing
substitution patterns from the nonaromatic compound to the
arene (Scheme 2b).6a Herein we report a novel strategy that
requires no harsh oxidants or transition metals and enables not
only regiochemical transfer but also concomitant regioselective
introduction of a halogen into the resulting arene (Scheme 2c).
We hypothesized that regioselective synthesis of monohalo-
genated, electron-rich arenes could be achieved by a halogen-
ation/aromatization cascade from unsaturated cyclic ketone
substrates (Scheme 3). Enones are poised for regiodivergent
functionalization through the corresponding dienolates that
possess multiple nucleophilic sites, and our strategy thus relies on
engaging these ambident nucleophiles in a regioselective
halogenation event. To address this regiocontrol issue, we
chose to incorporate an alkoxy group on the enone to enhance
electron density at the γ-carbon of the derived dienolate. There
have been only sparse reports of γ-selective transformations in
these systems,7−9 with the predominant literature describing α-
selective functionalization.10 Koreeda8 and Smith9 have explored
similar transformations but found an overall limited scope and
poor results for oxidation reactions. Our design also benefits
from the inherent differentiation of the two similarly reactive
resorcinol oxygen atoms, obviating a later synthetic challenge.11
Moreover, when coupled with Stork−Danheiser transforma-
Scheme 2. Strategies for Synthesis of Substituted Phenols and
Resorcinols
tions,10 the overall strategy could potentially functionalize all six
positions about the arene ring.
To test our hypothesis, we surveyed various base/halogen
donor combinations with readily available vinylogous ester 1a
(Table 1).9,10,12 Utilizing the conditions of Koreeda8 or Smith9
predominantly led to α-functionalized products in moderate
yield in the systems we examined. Although the majority of
amide bases led to nonhalogenated phenol products, we
observed that for compound 1a the use of lithium hexame-
thyldisilazide (LiHMDS) as base in the presence of polar
additives gave predominantly the haloarene 2, presumably
Received: December 9, 2014
Published: January 7, 2015
© 2015 American Chemical Society
378
DOI: 10.1021/ol503561x
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Letter
a
Scheme 3. Strategy for Regioselective Halogenation/
Aromatization Cascades
Table 2. Synthesis of 4- and 6-Haloresorcinols
a
Table 1. Optimization of Halogen Donors
a
Isolated yield of 2 from reactions with 1.0 mmol of substrate, 4.0
mmol of LiHMDS (1 M in THF), 2.1 mmol of X+ source, and 2.5
mmol of HMPA, in 10 mL of THF. 3-Ethoxyphenol is the major
b
product.
derived from the corresponding γ-dienolate, with hexamethyl-
phosphoramide (HMPA) providing the best results.13 The ratio
of α- to γ-functionalization was dependent on a number of factors
including concentration, temperature, and halogen donor.13,14
Using N-chlorosuccinimide or a N,N′-dichlorohydantoin, the
chlororesorcinol product predominated, but a significant amount
of nonhalogenated resorcinol formed as a side product (entries 1
and 2). Among the halogen donors surveyed, sulfonyl halides
emerged as especially effective, with the formation of only traces
of the nonhalogenated arenes.15 Aromatic sulfonyl chlorides
provided good results, with trisyl chloride performing the best
(entries 5−8).16 Alkyl sulfonyl chlorides provided only traces of
products (entry 4), but a sulfamoyl chloride performed well in
the reaction (entry 9). Bromo- and iodoresorcinols could be
accessed similarly by employing the corresponding tosyl
halides17 (entries 13 and 16), whereas the succinimide-based
halogen donors did not provide the same consistency over the
range of halides (entries 1, 10, and 14).18 We ultimately settled
upon a simple, one-pot procedure (conditions A, Table 2) that
transforms enone 1 into the chlorinated resorcinol 2a in 98%
yield with commercial TsCl as the halogen donor.13
We were pleased to find that many 4-haloresorcinol derivatives
could be formed following our protocol (Table 2). A reaction on
10 mmol scale occurs with no decrease in efficiency (2a).
Bromination and iodination reactions proceed in good yield as
well (2b, 2c, 2l, and 2m). A number of carbon-based substituents
are tolerated, including allyl and benzyl groups (2d and 2e) that
may not be compatible with conventional direct arene
halogenation protocols. We successfully synthesized differ-
entially functionalized diaryl ether 2f by employing a phenyl
ester substrate.19 Despite the basic reaction conditions, the Boc
group survives the transformation in fair yield (2g). Carbon
substituents about the ring cause no complications leading to
highly substituted arenes (2h−k). The mild sulfonyl halide
electrophile is compatible with oxidizable heteroatom-containing
a
Reactions performed with 1.0 mmol of substrate, 4.0 mmol of
LiHMDS (1 M in THF) total, and 2.1 mmol of Ts-X. For conditions
A, 2.5 mmol of HMPA and 10 mL of THF are used as solvent and
isolated yields are the average of three runs. For conditions B and C,
10 mL of solvent is used and isolated yields are the average of two
b
c
runs. Reaction on 10 mmol scale. Reaction on 5 mmol scale.
functional groups including thioethers and tertiary amines with
no evidence of oxidative decomposition (2l−n).
We next examined accessing 6-haloresorcinol derivatives by
modifying the reaction conditions. In the absence of HMPA the
6-haloresorcinol predominated, presumably via α-enolization/
halogenation similar to that described by Brummond.15e The
selectivity for the 6-halo isomer improved with nonpolar
cosolvents, with pentane performing the best in the chlorination
reaction (conditions B, Table 2). A variety of oxygen substituents
may be incorporated into the substrate, highlighted by acid-labile
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DOI: 10.1021/ol503561x
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Letter
t-Bu ether, oxidizable allyl ether, and carbonyl-containing
substrates (3b−e). Toluene proved to be the preferred solvent
to access bromo- and iodoarenes 3i−m (conditions C). Notably,
a β-sulfonyl enone20 proceeded to diaryl sulfone 3l with no
decrease in efficiency or change in regioselectivity.
Scheme 6. Aromatization/Mizoroki−Heck/Buchwald−
Hartwig Sequence
Since a phenoxide is a likely intermediate, we pursued trapping
of this nucleophile to access differentially protected resorcinol
derivatives (Scheme 4). We added electrophiles directly to the
nonaflate moiety. Subsequently, Pd-catalyzed Buchwald−
Hartwig amidation of the remaining aryl chloride was achieved
with a Buchwald-type biaryl phosphine ligand.27 Taken together,
this three-step sequence is a powerful, efficient means for
regiocontrolled formation of polysubstituted aromatics.
Scheme 4. One-Pot Aromatization/Phenoxide Trapping
Since the reaction involves two oxidation events, we sought to
establish the course of the halogenation reaction. Limiting the
amount of base led to isolation of a γ,γ-dichlorinated vinylogous
ester which aromatized upon exposure to hydroxide (Scheme 7).
Scheme 7. Isolation of Dichlorinated Intermediates
reaction mixture after complete aromatization had occurred and
found that tert-butyldimethylsilyl chloride (TBSCl) or chlor-
omethyl ethyl ether could be employed to prepare arenes 4 or 5,
respectively. These functionalized intermediates were each
previously synthesized from costly 4-bromoresorcinol in multi-
ple steps.21 We found that TsCl, AcCl, and BnBr are also suitable
trapping agents, providing a diversified platform for further
synthetic applications.
Haloarenes themselves are prevalent moieties in bioactive
natural products (see Scheme 1).1 However, we were also eager
to engage our haloaromatics in other synthetic transformations.
Claisen rearrangement22 of an allyl aryl ether leads to a 1,2,3,4-
substituted benzene with the halogen serving effectively as a
directing group (Scheme 5a). Transition-metal-catalyzed trans-
In the absence of HMPA, a similar sequence is observed via the
α,α-dichlorinated intermediate. Although the intermediacy of
α,γ-dichlorinated vinylogous esters cannot be rigorously
excluded, the likelihood of high regioselectivity in a putative
E2-type elimination step is small. Exposure of 3-methoxyphenol
to our reaction conditions did not lead to any haloarene
products, suggesting that halogenation precedes aromatization.
These results additionally indicate a delicate balance of the rates
of enolization/halogenation and the subsequent elimination step
that is essential for high yield of the haloresorcinol. Stronger
bases such as LDA are ineffective due to a combination of slow
introduction of the second halogen atom and poor performance
in elimination to form the arene. Similarly, succinimide-based
halogen donors appear to transfer a second halogen atom slowly,
allowing competitive elimination that leads to nonhalogenated
arene side products.
Scheme 5. Synthetic Transformations of Haloresorcinols
In conclusion, we have developed two regiodivergent
protocols that access specific halogenated resorcinol isomers in
a single operation from one readily available precursor without
transition metals or strong oxidants. These high-yielding
transformations provide ready access to halogenated aromatics
that are poised for further diversification. We anticipate that this
chemistry will find use in natural product synthesis, medicinal
chemistry, and materials synthesis, and we are currently pursuing
these applications.
formations including Mizoroki−Heck cyclization (Scheme 5b)23
and Sonogashira coupling (Scheme 5c)24 demonstrate the
potential to access functionalized heterocycles.25 Toward other
heterocyclic cores, regioselective Fries rearrangement of an
acylated resorcinol occurs upon exposure to Lewis acid and in
one further step a 4-chromone is formed (Scheme 5d).26
Given the recent advances in aryl chloride cross-coupling,2b we
explored chemoselective cross-couplings of our resorcinol
derivatives. To demonstrate this concept, we utilized our one-
pot aromatization/phenoxide trapping protocol with non-
afluorobutanesulfonyl fluoride (NfF) as an electrophile to access
a resorcinol derivative containing both a reactive aryl nonaflate
and a robust aryl chloride moiety (Scheme 6). Standard
Mizoroki−Heck reaction conditions23 led to reaction of the
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, and NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
380
DOI: 10.1021/ol503561x
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Letter
Tetrahedron Lett. 2004, 45, 4887−4890. (c) Bhatt, S.; Nayak, S. K. Synth.
AUTHOR INFORMATION
Corresponding Author
■
Commun. 2007, 37, 1381−1388. (d) Carreno, M. C.; García Ruano, J. L.;
̃
Sanz, G.; Toledo, M. A.; Urbano, A. Synlett 1997, 1241−1242.
(12) Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem., Int. Ed. 2006, 118,
3181−3184.
*E-mail: jtmohr@uic.edu.
Notes
(13) See the Supporting Information for details.
The authors declare no competing financial interest.
(14) To account for the formation of product mixtures, we suspect an
equilibrium exists between the two isomeric enolates.
(15) Few examples of sulfonyl chlorides as chlorenium donors appear
in the literature. For selected examples with enolates, see:
(a) Hakimelahi, G. H.; Just, G. Tetrahedron Lett. 1979, 20, 3643−
ACKNOWLEDGMENTS
■
Funding was provided through start-up funds from the UIC
Department of Chemistry. We thank Prof. Vladimir Gevorgyan,
Prof. Duncan Wardrop, and Prof. Daesung Lee (UIC) for helpful
discussions and use of reagents and analytical equipment.
Xiaoguang Liu (UIC) is acknowledged for aiding in collection of
characterization data.
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399−401. (c) Hirsch, E.; Hunig, S.; Reiβig, H.-U. Chem. Ber. 1982, 115,
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3687−3696. (d) Lee, K.; Shin, W. S.; Oh, D. Y. Synth. Commun. 1991,
21, 1657−1661. (e) Brummond, K. M.; Gesenberg, K. D. Tetrahedron
Lett. 1999, 40, 2231−2234.
(16) The reaction byproducts comprise a mixture of sulfur-containing
compounds that are most easily removed when trisyl chloride is used.
We chose to use TsCl for practical purposes.
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