6-Bromomethyl-4H-1,3-dioxin: A versatile bromomethyl vinyl ketone equivalent for heterocycle and carbocycle construction

Article abstract of DOI:10.1021/ja0123554

6-Bromomethyl-4H-1,3-dioxin has been prepared in three steps from allyl iodide. A variety of enolates were then alkylated with this bromide. The resulting 6-alkyl-4H-1,3-dioxins were either subjected to further multistep transformations and/or heated to e

Full text of DOI:10.1021/ja0123554

Published on Web 01/12/2002
6-Bromomethyl-4H-1,3-dioxin: A Versatile Bromomethyl Vinyl Ketone
Equivalent for Heterocycle and Carbocycle Construction
Thomas J. Greshock and Raymond L. Funk*
Department of Chemistry, The PennsylVania State UniVersity, UniVersity Park, PennsylVania 16802
Received October 15, 2001
Scheme 3
An intriguing strategy for hetero- or carbocycle synthesis involves
sequential reactions of doubly nucleophilic compounds with ha-
lomethyl vinyl ketones. However, only a few examples of this type
of cyclization have been reported,1 probably because of a lack of
selectivity between the â and R′ sites and sensitivity of these com-
pounds to basic reaction conditions conspire to render most strate-
gies problematical.2 These difficulties might be circumvented by
employing 6-bromomethyl-4H-1,3-dioxin (1, Scheme 1) as an
equivalent of bromomethyl vinyl ketone. Thus, the reactive allylic
halide moiety of bromide 1 was expected to smoothly participate
in substitution reactions and, moreover, permit the employment of
highly basic nucleophiles. Subsequently, the enone functionality
could be unveiled by a facile retrocycloaddition reaction of the 1,3-
dioxin ring3 to afford the generic compound 2 whose remaining
nucleophilic site could then be activated, if necessary, for conjugate
addition to afford the desired cyclic compounds 3. We disclose
herein the realization of this methodology and document its consid-
erable potential for the construction of natural product ring systems.
refluxing toluene to give the corresponding enones (12 h), products
requiring no chromatographic purification were obtained by per-
forming the reaction at higher temperatures for shorter periods of
time (toluene, sealed tube, 180 °C, 15 min). We were pleased to
find that the resulting enones underwent facile 7-endo ring closures
when subjected to reaction conditions (0.2 equiv of Cs2CO3, CH3-
CN, rt, 1-2 h) successful for related 7-endo ring closures using
exocyclic enolates of cyclic â-ketoesters.6 To the best of our
knowledge, these are the first examples of endo-Michael additions
of endocyclic enolates leading to seven-membered rings.7
We next turned our attention to annulation reactions using
bromide 1 (Scheme 4). The Weiler dianion of â-ketoester 9 and
the enolates of ketones 12, 15, 18, and 21 all gave good yields of
the corresponding alkylation products. Moreover, in several cases
the 1,3-dioxin moiety of the resulting products tolerated post-
Scheme 1
Scheme 4
The synthesis of bromide 1 (Scheme 2) commenced with the
preparation of 4-iodomethyl-1,3-dioxane (4) from allyl iodide
following a Prins cyclization protocol reported for the analogous
chloride.4 The iodide 4 was heated with solid KOH under reduced
pressure (55 °C, 160 mmHg) to afford 4-methylene-1,3-dioxane
(5) which distilled directly from the reaction mixture. The iodide-
leaving group is critical for the success of this elimination reaction
since similar treatment of 4-chloromethyl-1,3-dioxane4 required
higher temperatures and was accompanied by comparable amounts
of the endocyclic double bond isomer, 6-methyl-4H-1,3-dioxin.
Bromination of the enol ether 5 in the presence of Hu¨nig’s base
proceeded smoothly to provide the bromomethyl vinyl ketone
equivalent 1. The synthesis can be easily scaled to provide
multigram quantities of the stable bromide 1 and, in fact, is
accomplished in fewer steps than those required for the preparation
of bromomethyl vinyl ketone itself.1c
Scheme 2
We first examined the reactions of Weiler â-ketoesters dianions5
with bromide 1 (Scheme 3). Indeed, several â-ketoesters 6 cleanly
afforded the desired alkylation products 7. While the retrocycload-
dition reactions of the dioxins 7 proceed at an acceptable rate in
9
754 VOL. 124, NO. 5, 2002 J. AM. CHEM. SOC.
10.1021/ja0123554 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 6
alkylation modifications such as additional enolate formation (12
f 13 and 21 f 22) and the nucleophilic and acidic conditions of
the Stork-Danheiser enone synthesis8 (15 f 16 and 18 f 19).
The sequential retrocycloaddition reactions and Michael additions
of ketones 10, 13, and 16 all gave rise to bicyclo[4.3.1]decane-3,-
10-diones, (11, 14, and 17) the central substructure of the CP
compounds.9a,b Danishefsky’s recent report of annulation with
iodomethyl vinyl ketone and enamine derivatives of cyclohexanone
served as precedent1b for our complementary approach (alkylation
followed by conjugate addition) to the carbon framework of these
fascinating farnesyl transferase/squalene synthase inhibitors. Inter-
estingly, the rate of these cyclizations appears to correlate with the
pKa’s of the enolate precursors. The inability to identify a conjugate
addition product from the retrocycloaddition product of the des-
phenylthio corresponding to ketone 13 is in keeping with this trend.
Fused-bicyclic products are also accessible using this annulation
strategy. In contrast to 16, the γ-methyl carbon of the retrocy-
cloaddition product of enone 19 is activated by an ester substituent
and, consequently, furnishes a diastereomeric mixture of the fused
bicyclic diketo esters 20 upon completion of the annulation
sequence. In addition, a six-membered, fused-ring annulation was
effected by subjecting the retrocycloadduct of triflate 22 to Heck
reaction conditions10 to afford the dienone 23 as a single diaste-
reomer (see Supporting Information for diagnostic nOe’s).
then reduced stereoselectively (Scheme 6, BH3, -78 °C) to provide
only the equatorial alcohol 33. Removal of the Williams’ auxiliary
by the standard hydrogenolysis protocol11 then concluded a
relatively concise synthesis13 of the naturally occurring (2S,4R)-4-
hydroxypipecolic acid (34).
In conclusion, we have shown that readily available 6-bromo-
methyl-4H-1,3-dioxin (1) constitutes a useful bromomethyl vinyl
ketone equivalent. The exceptional reactivity of the allylic halide
moiety of dioxin 1 allows facile substitution by a variety of
nucleophiles. The 1,3-dioxin ring is sufficiently robust to permit,
if necessary, further multistep transformation of the alkylation
products. The potentially sensitive enone moiety can then be
released under mild, thermal conditions and, once generated,
smoothly participates in novel endo-conjugate addition reactions
with both carbon and nitrogen nucleophiles.
Acknowledgment. We appreciate the financial support provided
by the National Institutes of Health (GM28663). We thank Professor
Robert M. Williams of Colorado State University for a generous
sample of lactone 30.
We have also investigated the preparation of nitrogen-containing
heterocycles by the general strategy outlined in Scheme 1. To that
end, the alkylation of the carbanion derivatives of nitrile 24, ester
27, and the Williams lactone 3011 with bromide 1 all proceeded
uneventfully and furnished the expected dioxin-containing products
25, 28, and 31, respectively, in excellent yield (Scheme 5). As
Supporting Information Available: Spectroscopic data and exper-
imental details for the preparation of all new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
Scheme 5
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nitrile 24 and ester 27 alkylation products to arrive at the desired
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