Synthesis and derivatization of ethynyl α,α-dibromomethyl ketones: Formation of highly functionalized vinyl triflates

Article abstract of DOI:10.1021/ol027267i

(Matrix presented) We describe the synthesis of α,α -dibromomethyl ynones (8) and their subsequent derivatization to vinyl acetates (10). These vinyl acetates feature a 1,1-dibromo-olefin moiety, which is readily exploited in palladium-catalyzed Sonogashira, Stille, and Suzuki cross-coupling reactions with alkynes, stannanes, and boronic acids, respectively. A novel one-pot process then directly converts the resulting vinyl acetates 11-13 to the vinyl triflate derivatives 14a-j.

Full text of DOI:10.1021/ol027267i

ORGANIC
LETTERS
2003
Vol. 5, No. 2
213-216
Synthesis and Derivatization of Ethynyl
r,r-Dibromomethyl Ketones: Formation
of Highly Functionalized Vinyl Triflates
Trent Rankin and Rik R. Tykwinski*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta T6G 2G2, Canada
rik.tykwinski@ualberta.ca
Received November 11, 2002
ABSTRACT
We describe the synthesis of r,r-dibromomethyl ynones (8) and their subsequent derivatization to vinyl acetates (10). These vinyl acetates
feature a 1,1-dibromo-olefin moiety, which is readily exploited in palladium-catalyzed Sonogashira, Stille, and Suzuki cross-coupling reactions
with alkynes, stannanes, and boronic acids, respectively. A novel one-pot process then directly converts the resulting vinyl acetates 11−13
to the vinyl triflate derivatives 14a−j.
Vinyl triflates are versatile building blocks for the synthesis
of a diverse range of organic compounds.1,2 This is particu-
larly true as a result of the vast array of palladium-catalyzed
cross-coupling reactions developed for use with vinyl tri-
flates, including the Heck,3 Stille,4 Suzuki,5 and related cross-
coupling reactions.6
We have been interested in the use of suitably substituted
vinyl triflates as precursors for the iterative assembly of
extended, cross-conjugated oligomers and macrocycles.7 The
first generation of these highly unsaturated compounds was
derived from simple alkyl- or phenyl-substituted vinyl
triflates and afforded novel systems such as the iso-PDAs
(1) and expanded radialenes (2), as shown schematically in
Figure 1. For the synthesis of these oligomers, the requisite
vinyl triflates are accessible by using reported methods that
involve a sequence of Friedel-Crafts acylation of an acid
chloride (3) with bis(trimethylsilyl) acetylene to give ketone
4,8 followed by triflation with base and triflic anhydride to
give 5.9
In our quest for more highly functionalized derivatives of
1 and 2, however, synthetic routes appropriate to the
necessary vinyl triflates were unavailable. For example, per-
(ethynylated) derivatives of the triflate 5 (R ) CtCR′) would
be remarkably versatile modules for the construction of
conjugated oligomers, but the necessary precursors, R,R-
diethynyl carboxylic acids or acid chlorides 3, are to the best
of our knowledge an unknown class of molecules. Con-
versely, alkoxyl-substituted diaryl acetic acid chlorides (3,
R ) MeOC6H4) are available via reported methods.10
(1) Mitchell, T. N. Synthesis 1992, 803-815.
(2) Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85-
126.
(3) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7.
(4) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(5) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201-
2208
(6) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1997. (b) Rossi, R.; Carpita,
A.; Bellina, F. Org. Prep. Proc. Int. 1995, 27, 127-160. (c) Ritter, K.
Synthesis 1993, 735-762. (d) Scott, W. J.; McMurry, J. E. Acc. Chem.
Res. 1988, 21, 47-54.
(7) (a) Tykwinski, R. R.; Zhao, Y. Synlett 2002, 1939-1953. (b) Slepkov,
A. D.; Hegmann, F. A.; Zhao, Y.; Tykwinski, R. R.; Kamada, K. J. Chem.
Phys. 2002, 116, 3834-3840. (c) Campbell, K.; McDonald, R.; Tykwinski,
R. R. J. Org. Chem. 2002, 67, 1133-1140. (d) Zhao, Y.; Campbell, K.;
Tykwinski, R. R. J. Org. Chem. 2002, 67, 336-344. (e) Zhao, Y.; Campbell,
K.; Tykwinski, R. R. J. Org. Chem. 2002, 67, 2805-2812. (f) Zhao, Y.;
Tykwinski, R. R. J. Am. Chem. Soc. 1999, 121, 458-459. (g) Eisler, S.;
Tykwinski, R. R. Angew. Chem., Int. Ed. 1999, 38, 1940-1943.
(8) Walton, D. R. M.; Waugh, F. J. Organomet. Chem. 1972, 37, 45-
56.
(9) Stang, P. J.; Fisk, T. E. Synthesis 1979, 438-440.
10.1021/ol027267i CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/03/2003

with LDA at -78 °C, followed by reaction with either Et3-
SiCl or i-Pr3SiOTf to give 7a and 7b in excellent yields.
Employing the Barluenga protocol,13 reaction of esters 7a,b
with dibromomethyllithium (2 equiv), generated in situ from
LDA and CH2Br2, provided disappointingly low yields of
the dibromoketones 8a,b. Changing the reaction solvent to
Et2O and carefully quenching the reaction at low temperature,
however, substantially improved the outcome.14 Thus, ke-
tones 8a,b can be isolated in high yields, via rapidly passing
the impure reaction residue through a plug of silica. It is
worth noting that the reaction to 8a,b can be readily scaled
up (e.g., producing up to 6 g of 8a) and the products 8a,b
can be stored indefinitely under refrigeration (4 °C) without
observable decomposition.
Our initial efforts to derivatize the dibromo ketones 8a,b
targeted the synthesis of the silyl enol ether derivative 9. It
was envisioned that the dibromo olefin moiety of 9 would
be a suitable partner for subsequent palladium-catalyzed
cross-coupling reactions. Thus, dibromo ketone 8a was
readily converted to 9 in 91% yield via reaction with NEt3
and i-Pr3SiOTf in toluene (Scheme 2). All attempts at
Figure 1. Friedel-Crafts acylation based synthesis of ethynyl vinyl
triflates 5, the precursors to iso-PDAs (1) and expanded radialenes
(2).
Unfortunately, we have been unable to successfully convert
such acid chlorides to ethynyl ketones using either Friedel-
Crafts acylation or palladium-catalyzed coupling proce-
dures.11,12 As a result, we have developed, and report herein,
a general and versatile method for the formation of highly
functionalized vinyl triflate building blocks via the divergent
derivatization of ethynyl R,R-dibromomethyl ketones.
Trialkylsilyl protected propynone derivatives, the R,R-
dibromomethyl ynones 8a,b, were targeted as progenitors
to functionalized vinyl triflates (Scheme 1). To the best of
Scheme 2
alkynylation of 9 via Sonogashira cross-coupling15 have to
date been unsuccessful.16 It is quite likely that these reactions
fail due to the electron-rich nature of enol ether 9, which
would be expected to substantially retard this cross-coupling
reaction by slowing the oxidative addition of palladium into
the vinyl bromide bond.17
Scheme 1
In an attempt to provide a substrate that would facilitate
palladium-catalyzed cross-coupling reactions, an electron-
(14) General procedures. 8a: To a stirred solution of dibromomethane
(0.331 mL, 4.72 mmol) and 7a (500 mg, 2.32 mmol) in Et2O (10 mL) at
-78 °C was added LDA (4.72 mmol) in Et2O (10 mL) over a period of 10
min. The mixture was stirred for 20 min at -78 °C, and H2SO4 (0.25 mL)
in Et2O (2 mL) was then added; this mixture was stirred for 30 min at -78
°C. The now heterogeneous mixture was filtered through Celite, the organic
solvents evaporated, and the residue passed through a plug of silica gel
(hexane/EtOAc 30:1) to yield 8a (638 mg, 81%) as a light yellow oil. 10a:
Compound 8a (457 mg, 1.34 mmol) in THF (10 mL) was cooled to -78
°C, LiHMDS (1.61 mmol) in THF (5 mL) was added, and the mixture was
stirred for 30 min at -78 °C. Ac2O (0.190 mL, 206 mg, 2.02 mmol) was
added, and the mixture was allowed to warm to room temperature over a
period of 4 h. The reaction was quenched with saturated NH4Cl (10 mL)
and extracted with Et2O (2 × 20 mL), and the organic layer was washed
with brine (20 mL), dried (Na2SO4), filtered, and evaporated. The residue
was purified by filtration through a plug of silica gel (hexane/Et2O 20:1) to
yield 10a (499 mg, 1.31 mmol, 97%) as an amber oil.
our knowledge, 1,1-dibromo-4-phenyl-2-butynone is the only
analogue of 8 that has been reported in the literature,13 and
it was synthesized from the 3-phenyl ethyl propynoate. With
the intent of emulating this reported procedure, the terminal
alkyne of ethyl propynoate (6) was silylated via deprotonation
(15) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470.
(10) Baarschers, W. H.; Vukmanich, J. P. Can. J. Chem. 1986, 64, 932-
935.
(16) Unsuccessful conditions include Pd(PPh3)4 or PdCl2(PPh3)2, Et3N
or i-Pr2NH (with or without THF cosolvent), CuI, at reflux. More active
catalysts such as that reported by Fu and Buchwald, however, have not yet
been attempted, see: Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu,
G. C. Org. Lett. 2000, 2, 1729-1731.
(11) Verkruijsse, H. D.; Heus-Kloos, Y. A.; Brandsma, L. J. Organomet.
Chem. 1988, 338, 289-294.
(12) Chernick, E. T.; Tykwinski, R. R. Unpublished results.
(13) Barluenga, J.; Llavona, L.; Concello´n, J. M.; Yus, M. J. Chem. Soc.,
Perkin Trans. 1 1991, 297-301.
(17) Singh, R.; Just, G. J. Org. Chem. 1989, 54, 4453-4457.
214
Org. Lett., Vol. 5, No. 2, 2003

Scheme 3 a
Scheme 4 a
a Reagents and conditions: (a) LiHMDS, Ac2O, THF, -78 °C;
(b) NEt3, Ac2O, DMAP, THF, rt.
withdrawing enol protecting group was targeted. Thus,
ketones 8a,b were converted in excellent yields to vinyl
acetates 10a,b via deprotonation with LiHMDS at -78 °C,
followed by reaction with acetic anhydride (method a,
Scheme 3). Alternatively, for large-scale production of 10a
it was determined that a comparable yield could be obtained
with NEt3 and acetic anhydride (method b).18 The acetates
10a,b were easily purified via passing the reaction mixture,
following work up, through a short plug of silica gel, and
both 10a and 10b are stable indefinitely under refrigeration.
Palladium-catalyzed cross-coupling reactions with vinyl
acetates 10a and 10b were considerably more successful than
those attempted for enol ether 9.19 Sonogashira cross-
coupling of 10a with terminal alkynes at room temperature
required reaction times of ca. 24 h with a slight excess of
the alkyne and PdCl2(PPh3)2 as the catalyst (Scheme 4).
Under these conditions, the triyne products 11a-c, incor-
porating triisopropylsilyl, phenyl, and ferrocenyl actylenes,
respectively, were generated and isolated in good yields by
column chromatography on silica; all are stable.
Equally successful was the use of acetate 10a in palladium-
catalyzed Suzuki cross-coupling with boronic acids.20 With
use of Pd(PPh3)4 as catalyst and K2CO3 as the base, the
diarylated vinyl acetates 12a-d were produced in yields of
50-85% (Scheme 4). These reactions were complete in less
than 24 h at 110 °C. It is noteworthy that both the vinyl
acetate and triethylsilyl moieties tolerate these reaction
conditions, as long as the reaction is kept strictly anhydrous.
As for 11a-c, the products 12a-d were easily isolated by
column chromatography.
a Reagents and conditions: (a) HsCtCsR, PdCl2(PPh3)2, CuI,
NEt3, rt; (b) (HO)2BsAr, Pd(PPh3)4, K2CO3, 110 °C; (c) DMF,
ArSnBu3, Pd(PPh3)4, 120 °C.
Direct conversion of triyne vinyl acetates 11a-c to the
corresponding ketones was attempted by employing a number
of methods known to effect acetate removal, including
reaction with KCN, MeLi, and Mg(OMe)2.21 Spectral
evidence (1H NMR and IR spectroscopies) suggested that
the generation of the desired R,R-diethynylated ketones had
been successful. All attempts toward isolation of pure
material were unproductive, however, due to an inherent
instability of the products, presumably the result of facile
isomerization to the R-allenyl ketones.22
As a result, a direct conversion sequence from acetate to
the desired triflates 14a-c was explored (Scheme 5). It was
anticipated that the enolate resulting from removal of the
acetate moiety could be trapped in situ,23 via reaction with
an appropriate triflating reagent.24 Several combinations of
deprotection reagents (t-BuOK, MeLi) and triflate sources
(PhNTf2, Tf2O) were employed, with varying levels of
success. Ultimately, optimized conditions for this process
were developed based on acetate removal with MeLi in THF
at low temperature, followed by reaction with triflic anhy-
dride, also at low temperature. Overall isolated yields over
these two steps for 14a-c were quite good, ranging from
60 to 81%. Contrasting the instability encountered with the
corresponding ketones, vinyl triflates 14a-c are stable and
easily handled.
Elaboration of acetate 10a to heteroaryl-substituted vinyl
acetates was possible through the use of Stille cross-coupling
methods. The use of aryl trialkylstannane precursors can be
advantageous due to their more facile synthesis in compari-
son to many boronic acids, which can be difficult to purify.
Vinyl acetates 13a-c were prepared with Pd(PPh3)4 as
catalyst in DMF at 120 °C with reaction times of 2-4 h
(Scheme 4). All products were isolated by column chroma-
tography on silica gel as stable oils.
The ketones derived from 12a-d and 13a-c would be
expected to be stable, potentially allowing for a stepwise
(21) (a) Mori, K.; Tominaga, M.; Takigawa, T.; Matsui, M. Synthesis
1973, 790-791. (b) Xu, Y.-C.; Bizuneh, A.; Walker, C. Tetrahedron Lett.
1996, 37, 455-458.
(22) R-Ethynylated ketones are known to be stable, see: Arisawa, M.;
Amemiya, R.; Yamaguchi, M. Org. Lett. 2002, 4, 2209-2211 and references
therein.
(23) Duhamel, P.; Cahard, D.; Poirier, J.-M. J. Chem. Soc., Perkin Trans.
1 1993, 2509-2511.
(24) (a) McMurray, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-
982. (b) Dunn, P. J.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1987,
1585-1592.
(18) Cousineau, T. J.; Cook, S. L.; Secrist, J. A., III Synth. Commun.
1979, 9, 157-163.
(19) Palladium-catalyzed couplings were optimized with vinyl acetate
10a because of the more facile removal of the triethylsilyl in comparison
to the triisopropylsilyl moiety. Transformations conducted with derivative
10b under analogous conditions have been equally successful.
(20) Shieh, W. C.; Carlson, J. A. J. Org. Chem. 1992, 57, 379-381.
Org. Lett., Vol. 5, No. 2, 2003
215

transformations are on the order of 30 min, and the products
are readily isolated in good to excellent yields by column
chromatography.
Scheme 5
In conclusion, we have outlined general conditions for the
synthesis of highly unsaturated, functionalized vinyl triflate
building blocks. The compatibility of the dibromovinyl
acetate 10a with the Sonogashira, Stille, and Suzuki cross-
coupling conditions allows for the rapid, divergent elabora-
tion to a range of 2,2-diethynyl and -diaryl derivatives. These
vinyl acetates, 11-13, can then be directly converted to vinyl
triflates 14, in a one-pot sequence of acetate removal and
triflation. The propensity of several of these novel vinyl
triflate products to be elaborated into extended oligomeric
systems such as 1 and 2 is being investigated and will be
reported in due course.
sequence of acetate removal and subsequent triflate forma-
tion, as in Figure 1 (4 f 5). From a practical standpoint,
however, a stepwise route was problematic, due to difficulties
anticipated in the conversion of the ketone to the desired
vinyl triflate. For example, standard protocol for the forma-
tion of 14d (R ) C6H5) directly from the ynone precursor
requires reaction times on the order of 1 week and affords
yields of ca. 50%.9
Acknowledgment. Financial support for this work from
The University of Alberta and the National Science and
Research Council of Canada is gratefully acknowledged.
Thus, the facile, one-pot reaction sequence successful in
the formation of 14a-c was applied to diaryl precursors
12a-d and heteroaryl compounds 13a-c. Subjecting 12a-d
or 13a-c to 2 equiv of MeLi at -78 °C effected enolate
formation, and the subsequent addition of triflic anhydride
provided vinyl triflates 14d-j. Reaction times for these
Supporting Information Available: Synthetic and char-
1
acterization details; H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Org. Lett., Vol. 5, No. 2, 2003