Ynol ethers from dichloroenol ethers: Mechanistic elucidation through 35Cl labeling

Article abstract of DOI:10.1021/ol801704u

(Chemical Equation Presented) The mechanism of ynol ether formation from dichloroenol ethers, a decades-old transformation, has been studied by experimental and theoretical techniques to determine the relative importance of the Fritsch-Buttenberg-Wichell rearrangement (α-elimination) and β-elimination in the evolution of the intermediate carbenoid.

Full text of DOI:10.1021/ol801704u

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4445-4447
Ynol Ethers from Dichloroenol Ethers:
35
Mechanistic Elucidation Through Cl
Labeling
Benjamin Darses, Anne Milet, Christian Philouze, Andrew E. Greene, and
Jean-Franc¸ois Poisson*
De´partement de Chimie Mole´culaire (SERCO), UniVersite´ Joseph Fourier, UMR-5250,
ICMG FR-2607, CNRS BP 53, 38041 Grenoble Cedex 9, France
jean-francois.poisson@ujf-grenoble.fr
Received July 25, 2008
ABSTRACT
The mechanism of ynol ether formation from dichloroenol ethers, a decades-old transformation, has been studied by experimental and theoretical
techniques to determine the relative importance of the Fritsch-Buttenberg-Wichell rearrangement (r-elimination) and ꢀ-elimination in the
evolution of the intermediate carbenoid.
Ynol ethers are a useful and well-studied class of compounds
that have often been employed in synthesis, in particular for
the preparation of enol ethers.1 The most convenient and
frequently used method for their preparation employs the
corresponding dichloroenol ethers I (Scheme 1).2 These
ethers are easily obtained through the addition of alkoxides
to dichloroacetylene, a transformation applicable to a wide
variety of alcohols. The ynol ethers are readily synthesized
by reaction of the dichloroenol ethers with 2 equiv of
n-butyllithium, leading to the intermediate lithioacetylide III,
which is subsequently trapped with an electrophile.2 Despite
the use of this effective procedure for decades by numerous
practitioners,3 its mechanism, surprisingly, is still debated.
A probable, but still hypothetical, lithio-chloro carbenoid
II, formed through vinylic proton abstraction by n-butyl-
lithium, would be expected to evolve by one, if not
competitively two, mechanistic pathways: Fritsch-
Buttenberg-Wischell (FBW) rearrangement (formally
(1) For reviews, see: (a) Arens, J. F. In AdVances in Organic Chemistry;
Raphael, R. A., Taylor, E. C., Wynberg, H., Eds.; Interscience Publishers,
Ltd: New York, 1960; Vol. II, pp 117-212. (b) Rachenko, S. I.; Petrov,
A. A. Russ. Chem. ReV. 1989, 58, 1671–1702. For more recent publications,
see refs 3a-g.
Scheme 1. Ynol Ether Formation from Dichloroenol Ethers
(2) (a) Normant, J. F. Bull. Soc. Chim. Fr. 1963, 1876–1897. (b) Moyano,
A.; Charbonnier, F.; Greene, A. E. J. Org. Chem. 1987, 52, 2919–2922.
(c) Kann, N.; Bernardes, V.; Greene, A. E. Org. Synth. 1997, 14, 13.
(3) There are over 100 citations of refs 2a-c. For selected recent papers,
see: (a) Harmata, M.; Lee, D. R.; Barnes, C. L. Org. Lett. 2005, 7, 1881–
1883. (b) Ceccon, J.; Poisson, J.-F.; Greene, A. E. Synlett 2005, 8, 1413–
1416. (c) Roche, C.; Kadlecikova, K.; Veyron, A.; Delair, P.; Philouze, C.;
Greene, A. E. J. Org. Chem. 2005, 70, 8352–8363. (d) Clark, J. S.; Kimber,
M. C.; Robertson, J.; McErlean, C. S. P.; Wilson, C. Angew. Chem., Int.
Ed. 2005, 44, 6157–6162. (e) Bandur, N. G.; Bru¨ckner, D.; Hoffmann,
R. W.; Koert, U. Org. Lett. 2006, 8, 3829–3831. (f) Ceccon, J.; Greene,
A. E.; Poisson, J.-F. Org. Lett. 2006, 8, 4739–4742. (g) Clark, J. S.; Grainger,
D. M.; Ehkirch, A. A.-C.; Blake, A. J.; Wilson, C. Org. Lett. 2007, 9, 1033–
1036.
R-elimination-migration)4 and/or cis ꢀ-elimination (Scheme
1). Herein, we present the first experimental proof, as well
10.1021/ol801704u CCC: $40.75
Published on Web 09/18/2008
2008 American Chemical Society

as a metadynamics study, of the mechanism of ynol ether
formation from dichloroenol ethers.
and/or cis ꢀ-elimination. The FBW rearrangement is com-
monly advanced to explain alkyne formation from alkenyl
halides (e.g., the Corey-Fuchs reaction10), and furthermore,
chlorine migration is known to be a facile process;11 cis
ꢀ-elimination, albeit less energetically favorable than trans,
is also precedented.12 A novel approach allowed us to resolve
this dichotomy of possible pathways.
It was recognized that in a ꢀ-elimination process, the
remaining chlorine atom would be the carbenoid one (in
green, eq 1), but in the case of a FBW rearrangement, the
other chlorine (in red) would be that found in the final
product.
Since the configuration of enol ethers formed through the
addition of metal alkoxides to dichloroacetylene was not on
firm ground,5 but relevant, it was first addressed. Fortunately,
dichloroenol ether 1 could be crystallized and its structure
determined by X-ray crystallography, which established the
previously assumed E configuration (Scheme 2).6 Deproto-
Scheme 2. X-ray Structures of E-Enol Ethers 1 and 2
To determine which process (if not both) was operative,
the ideal solution would therefore be to replace selectively
one of the chlorines with an isotopically enriched one, either
35 or 37. Mass spectrometry of chloroynol ether 3 could
then be used to identify the chlorine isotope(s) and thereby
the mechanism. For the synthesis of such a labeled molecule,
chloroynol ether 3 was chosen in the hope that it might
cleanly and selectively undergo hydrochlorination,13 in spite
of the acid sensitivity of both the ynol and dichloroenol
ethers. In the event, hydrochlorination of compound 3 with
a 1 M solution of H35Cl in ether (from Na35Cl, 99 atom %)
could be cleanly achieved with careful temperature control
to give the corresponding dichloroenol ether, uniquely E, in
54% yield (Scheme 4). The mass spectrum of 1-35 displayed
nation, as opposed to implausible chlorine-lithium ex-
change,7 was next confirmed: treatment of 1 at -78 °C with
a single equivalent of n-butyllithium, followed by the
addition of methyl iodide, led to the methyl-substituted
derivative 2 in excellent yield. The low-temperature con-
figurational stability of the intermediate lithium carbenoid
was evidenced by X-ray structure analysis of this product
(Scheme 2), a finding in accord with the reported high energy
required for isomerization of simple vinylic carbenoids.8
When the above solution containing the lithium carbenoid
was allowed to warm, however, the corresponding chloroynol
ether 3 could be isolated in high yield (Scheme 3).9 The
Scheme 4.
35Cl-Labeling Experiment
Scheme 3. Formation of Chloroynol Ether 3
formation of the acetylene begins at -65 °C (6.6:1 1:3 after
5 min) and the transformation is complete after 10 min at
-50 °C. Thus, the second equivalent of n-butyllithium plays
no role in acetylene formation but serves to generate the
lithioacetylide by chlorine-lithium exchange.7
Armed with the knowledge that dichloroenol ether 1
undergoes conversion to the chloroynol ether 3 through an
E-lithium carbenoid that is stereostable at low temperature,
complete elucidation of the mechanism was reduced to
determining the evolution of carbenoid:FBW rearrangement
the expected 3:1 ratio of molecular ions at 293 and 295 (M
+ Na)+, confirming the introduction of a single chlorine-35
into the molecule. Exposure of 1-35 to 1 equiv of n-
butyllithium (-78 f -10 °C) led to the chloroynol ether 3.
The CI mass spectrum of 3 revealed a 3:1 ratio of low-
intensity molecular ions at 235 and 237 (MH)+, respectively,
4446
Org. Lett., Vol. 10, No. 20, 2008

indicative of predominant loss of the 35Cl atom and proof
that ꢀ-elimination is the major pathway. However, since the
chlorine isotope ratio in chloroynol ether 3 reflects the extent
of participation of the two mechanistic pathways, greater
precision in the isotope ratio measurement was required. To
this end, chloroynol ether 3 was hydrolyzed with sulfuric
acid in THF to yield the R-chloro acetate 4. ESI mass
spectrometry (triple quadrupole analyzer) of 4 indicated with
high precision an isotopic ratio that corresponded exactly to
the theoretical ratio (100:33.6) for the nonlabeled product,
clear proof that cis ꢀ-elimination, and uniquely cis ꢀ-elim-
ination, is operatiVe in this transformation.14
11 kcal/mol. The 5 kcal/mol difference between the two
mechanisms is fully concordant with the experimentally
determined single pathway.
In conclusion, after nearly half a century and considerable
application, it has unambiguously been shown through
chlorine-35 labeling that the formation of ynol ethers from
dichloroenol ethers does not proceed by FBW rearrangement,
but exclusively through cis ꢀ-elimination. Metadynamics
calculations, furthermore, have confirmed the substantial
energy difference between these two mechanisms.
Acknowledgment. This article is dedicated to Prof. J.
Normant. We thank Prof. P. Dumy (UJF) for his interest in
our work, the French Ministry of Research for a fellowship
(to B.D.), and the CECIC for providing computer facilities.
Metadynamics ab initio calculations15 have also been
carried out to gain a better appreciation of the free-energy
requirements for the elimination pathways. While few
theoretical studies have been realized to date on R- and
ꢀ-eliminations in carbenoids, and none using metadynamics,
this recently developed calculation method has already been
used successfully for solving other problems in organome-
tallic chemistry.16 The calculated trajectory, interestingly,
reveals a shortening of the RCl-Li distance, close to values
relevant for bond formation in a FBW event, twice during
the evolution (1000 and 1700 fs, Figure 1). However, the
Supporting Information Available: Complete experi-
1
mental procedures, characterization data, and H and 13C
NMR spectra for compounds 1-35 and 2-4, metadynamics
calculation details (including a videoclip of the trajectory),
and a crystallographic information file for X-ray analysis of
1 and 2. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL801704U
(4) (a) Fritsch, P. Liebigs Ann. Chem. 1894, 279, 319. (b) Buttenberg,
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Chem. 1894, 279, 337. For reviews, see: (d) Knorr, R. Chem. ReV. 2004,
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(6) The configuration of the corresponding stericol derivative3b,c,f was
also found to be E.
(7) Clayden, J. In Organolihtiums: selectiVity for synthesis; Baldwin,
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630.
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to be unstable.
(10) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769–3772.
(11) Ochiai, M.; Uemura, K.; Masaki, Y. J. Am. Chem. Soc. 1993, 115,
2528–2529.
(12) Cristol, S. J.; Bly, R. S., Jr. J. Am. Chem. Soc. 1961, 83, 4027.
(13) For the hydrochlorination of simple ynol ethers, see: Yu, W.; Jin,
Z. J. Am. Chem. Soc. 2000, 122, 9840–9841.
Figure 1
distances.
. Metadynamics calculation results: evolution of Cl-Li
(14) This measurement was realized in the mass spectrometry laboratory
of the Universite´ Pierre et Marie Curie (Paris VI). The major isotope had
a relative intensity of 100%; the precision of the result is within 1% of the
intensity of the minor mass. This same technique could not be applied to
compound 3 due to a lack of ionization.
final lowest energy pathway involves, as now expected,
ꢀCl-Li bond formation. The calculated total free energy of
activation for the pathway is 6 kcal/mol, consistent with the
fast reaction that is experimentally observed at low temper-
ature. The meta-trajectory of the FBW pathway was also
simulated and indicated a total free energy of activation of
(15) (a) Laio, A.; Parrinello, M. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
12562–12566. (b) Laio, A.; Rodriguez-Fortea, R.; Gervasio, F. L.; Ceccarelli,
M.; Parrinello, M. J. Chem. Phys. B 2005, 109, 6714–6721.
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