Intramolecular carbolithiation of alkynes: Anti selectivity

Article abstract of DOI:10.1002/anie.200704139

(Chemical Equation Presented) A stereochemical twist in the tale: The treatment of the propargylic acetal 1 with one equivalent of n-butyllithium provided the dihydrobenzofuran 2 with an exocyclic E double bond. The results of DFT calculations suggest tha

Full text of DOI:10.1002/anie.200704139

Angewandte
Chemie
DOI: 10.1002/anie.200704139
Organolithium Chemistry
Intramolecular Carbolithiation of Alkynes: anti Selectivity**
Catherine FressignØ,* Anne-Lise Girard, Muriel Durandetti, and Jacques Maddaluno*
Dedicated to Professor Miguel Yus on the occasion of his 60th birthday
Carbometalation reactions, which involve the addition of an
À
organometallic reagent across a C C multiple bond, are
among the simplest methods for functionalizing olefins and
alkynes.[1] Organolithium derivatives are well known to
promote these transformations and have proved particularly
useful for cyclization and heterocyclization steps, as demon-
Scheme 1. Stereoselective anti intramolecular carbolithiation of 1.
strated elegantly by Bailey and co-workers,[2] Negishi and co-
workers,[3] and others.[4] We reported previously a simple
process for the conversion of propargylic ethers into 3-
vinylbenzofuranes, furopyridines, and indoles through a
carbolithiation–elimination sequence;[5] however, the mecha-
nism of this efficient reaction remained unexplored. We now
report experimental and theoretical details concerning the
carbolithiation step and its unexpected stereochemical
course.
We chose to focus our study on the model case of the
formation of the dihydrobenzofuran 2 in an attempt to
characterize some of the intermediates along the reaction
pathway. Previous studies had shown that a significant excess
of n-butyllithium (3 equiv) was necessary for the reaction to
reach completion. However, the role played by this reagent
was unclear. In fact, upon the addition of exactly one
equivalent of nBuLi, 3-(2,2-diethoxyethylidene)-2,3-dihydro-
benzofuran (2) was recovered in good yield (Scheme 1).
Careful bidimensional NMR spectroscopic analysis in
deuterotoluene[6] showed that 2 was obtained solely as the
E isomer, which suggested that addition to the alkyne had
occurred in an anti fashion. To our knowledge, the anti
addition of an organolithium reagent to an alkyne has never
been reported previously. When the reaction was quenched
with EtOD instead of water, the expected deuterated
exocyclic alkene was obtained with 34% labeling. When
diethyl ether was used as the solvent, 2 was still formed at
À788C with E selectivity, but in poor yield (12%, 78%
labeling). Thus, one equivalent of nBuLi is sufficient to trigger
the cyclization but does not elicit the b elimination of lithium
ethoxide.
This puzzling stereochemical result prompted us to
undertake a DFT computational study of the carbometalation
step. This reaction has seldom been the object of theoretical
studies.[7] We simplified our model slightly by replacing the
ethyl acetal with a methyl acetal and selected the B3P86
functional and the 6-31G** basis set on the basis of our
previous results in this field.[8] Zero-point energy (ZPE)
corrections were included in the computations. The electron-
localization function (ELF) used relies on a topological
approach of the chemical bond.[9] Such an electron distribu-
tion, which implicitly takes into account the superposition of
the resonance forms, provides useful information on the
electron reorganization induced by the rearrangement of the
intermediates.[10]
[*] Dr. C. FressignØ, Dr. A.-L. Girard, Dr. M. Durandetti, Dr. J. Maddaluno
Laboratoire des Fonctions AzotØes & OxygØnØes Complexes
de l’IRCOF
UMR CNRS 6014
UniversitØ et INSA de Rouen
76821 Mont St Aignan Cedex (France)
Fax: (+33)2-3552-2971
The model considered in this study was the lithiated aryl
compound 1–Li derived from 1[11] and solvated by two explicit
molecules of THF. We chose this model to ensure tetracoor-
dination to the lithium ion, which is surrounded initially by
E-mail: cfressig@crihan.fr
jmaddalu@crihan.fr
CAr and one oxygen atom of the acetal. The full optimization
Dr. C. FressignØ
Laboratoire de Chimie ThØorique
of 1–Li 2THF led to a “folded” conformer in which the triple
bond faces the lithium cation.[12] In the conformer that reacts
via the lowest-energy transition state (TS), coordination
between one of the oxygen atoms of the acetal and the cation
was also observed (Li–O(acetal): 2.16 Š). The TS was then
localized through a potential-energy scan (PES) by decreas-
ing the C(Ar)–C(1) distance (Scheme 1). The reoptimization
of this primary TS led to the identification of an early
transition state in which the coordination of the lithium ion to
the three oxygen atoms is conserved (Figure 1). The relatively
low energy barrier of 8.3 kcalmolÀ1 to the formation of this
transition state is compatible with a rapid reaction at À788C.
Further shortening of the reaction coordinate provided the
´
UMR 7616 CNRS
´
UniversitØ P. A&M. Curie, Case Courrier 137
4, Place Jussieu
75252 Paris Cedex 05 (France)
[**] Computations were carried out at CRIHAN (St Etienne-du-Rouvray,
France) and CINES (Montpellier, France). A.L.G. acknowledges the
PUNCHorga interregional network for a PhD fellowship. We thank
Prof. Hassan Oulyadi (UniversitØ de Rouen, France) for his help and
spectroscopic contributions to this program, as well as Prof. Ilan
Marek (Technion, Israel) and Fabrice Chemla (UniversitØ Paris VI,
France) for discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
parallel to the newly formed benzofuran nucleus. The third
snapshot shows the continuation of this movement with the
pivoting of the acetal group to accompany the lithium ion. In
the fourth snapshot, an intermediate similar to the condensa-
tion product is observed in which the E double bond has
formed and the C(2)–Li distance has reached its final value.
Thus, it seems that the robust Li–O(acetal) coordination,
which diverts the reaction from its usual course, explains the
anti character of this carbolithiation and the final configu-
ration of the double bond.
In 2–Li, the flexible interactions between the lithium ion
and C(2) together with the Li–O(acetal) interaction keep the
cation in a tetracoordinated state and approximately 308
outside the plane of the heterocycle and the double bond
(C(Ar)-C(1)-C(2)-Li: 2118; C(1)-C(2)-Li: 1488). The effect of
the observed coordination is also illustrated by the cyclization
of a folded conformer[11] in which the Li–O(acetal) interaction
does not take place (Figure 3). In this case, a later and higher-
Figure 1. Energy diagram for the cyclization of 1–Li 2THF into
(E)-2–Li 2THF; green C, white H, red O, orange Li.
expected E dihydrobenzofuran 2–Li after a considerably
exothermic reaction (DrH < À45 kcalmolÀ1).
To gain better insight into the origin of this unusual
E selectivity, we next focused our attention on the evolution
of the system between the TS and 2–Li. Four snapshots
extracted from the PES are displayed in Figure 2. The first
Figure 3. Uncoordinated conformer of 1–Li (left) and the transition
state for its cyclization (right).
energy TS (+ 11.4 kcalmolÀ1) is found in which the triple
bond is bent to prefigure the future Z olefin.
In conclusion, the bromoaryl compound 1 is transformed
stereoselectively upon treatment with n-butyllithium
(1 equiv) into the dihydrobenzofuran 2. The reaction pro-
ceeds via a low-lying transition state responsible for the anti
addition to the alkyne. DFT calculations suggest that intra-
molecular coordination of the lithium cation by one oxygen
atom of the terminal acetal appendage is responsible for this
previously unobserved stereochemical outcome. The O–Li
interaction is observed throughout the cyclization and drives
the cation to the appropriate site on the double bond, finally
leading to the formation of the E product upon hydrolysis.
Complementary calculations show that in the absence of this
coordination (as in the conformer depicted in Figure 3), the
Z olefin that results from a classical syn addition should be
obtained via a transition state with a higher energy barrier.
Overall, these data suggest that the stereochemical outcome
of such carbolithiation reactions could be controlled through
the appropriate design of the substrate.
Figure 2. Four snapshots along the cyclization of 1–Li. In the ELF
representations (right), the cores are shown in magenta, the mono-
synaptic and disynaptic valence basins in red and green, respectively,
and the hydrogen atoms in blue.
illustrates the situation when the distance from C(Ar) to the
lithium atom has increased by about 0.1 Š with respect to that
À
in the TS. Thus, the largely ionic C(Ar) Li bond lengthens,
and the Li ion moves so that the plane in which it is
coordinated to the three oxygen atoms is nearly parallel with
the plane of the aromatic ring. The persisting acetal coordi-
nation forces the forming double bond to adopt an E config-
uration. Simultaneously, the lone pair of electrons is localized
on C(2), whereas a valence basin appears between C(Ar) and
Received: September 7, 2007
Published online: December 14, 2007
À
C(1). In the next step, the C(Ar) C(1) bond is reinforced, and
the lithium coordination plane continues its movement
Keywords: alkynes · carbolithiation · cyclization ·
density functional calculations · diastereoselectivity
.
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Chemie
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.
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