Projets de recherche
Benoit Daoust
RESEARCH PROJECTS :
1. Radical addition towards ynol ethers
Context : Carbon-carbon bond formation by radical and ionic addition of haloalkanes to enol ethers
and silyl ynol ethers has attracted the attention of chemists (1-5). However, before our preliminary
results, addition of haloalkanes to ynol ethers was, to the best of our knowledge, unknown.
Objective : The objective is to evaluate the potential of radical additions to ynol ethers as a very mild
and stereoselective method of synthesizing useful functionalities such as -halo enol ethers, important
acyl anion equivalents (6), and -oxy enamides.
Methodology : Our working hypothesis was that radical addition of halogenated active methylene 1 (Z
= CO2R, CF3, SO2R, CN) (Scheme 1) to ynol ethers 3 would lead to -halo enol ethers 5 via the vinyl
radical 4. The use of bromides or iodides (X = Br, I) which are efficient halogen-atom transfer agents
should ensure rapid trapping of the vinyl radical 4 before its isomerization and give mainly E isomer 5.
RO
XCH2Z
1
Et3B
-X
R'
3
ZCH2
R'
CH2Z
Solvent
Et3B
2
R'
CH2Z
"X "
X
OR
OR
5
4
(E-isomer)
Scheme 1
Our preliminary results showed that addition of haloalkanes 1 (X = I, Z = CO2Ph, CO2Me) to ynol
ethers 3 (R' = H, R = Et, menthyl) led to -iodoenol ether 5 with efficiency (60-80 % yield),
stereospecificity (only the E isomer was observed) and rapidity (completion within 10 minutes at 78°C).
Our next objective will be to synthesized ynol ethers with various R' groups differing in steric bulk (R'
= H, CH3, i-C3H7, t-C4H9) and electronic properties (R' = CH3, CF3, COCH3, SiR3) in order to evaluate
their effect on the reactivity and stereoselectivity.
Z
Z
X
Et3B
RO
RO
7
X
8
Scheme 3
An intramolecular version of this powerful methodology (see Scheme 3) will also be studied. For
example, 5-exo-dig cyclization of compound 7 should produce stereoselectively exocyclic enol ether 8
under smooth conditions. The interesting -halo -alkoxycycloalkylidene moiety produced by this
reaction will be used for the construction of triquinane compounds (see Long-Term Objectives). Exoadducts 8 (X = H) are precursors of exocyclic dihydroxyacetones, a structural unit common to the
corticoid hormones (7). The mildness of the reaction conditions of this new method for preparing halo enol ethers presents a great advantage over the few existing methods (8). For instance, these
methods require acidic reaction conditions, which can be deleterious to a number of -halo enol ethers.
Another benefit of this new methodology is that it does not require aqueous work-up which is known
to trigger decomposition of certain classes of halo enol ethers (8). We will also investigate the
possibility of preparing -oxy enamides as amino acid precursors by addition of ZCONRX (X = Cl,
SPh, OCOPh, PTOC ; Z = EWG) to ynol ethers (Scheme 4). This reaction should be successful and
occur through a radical process since it has been shown that the N-haloamides add efficiently to enol
ethers in a chain-radical reaction (9). Here again, the double bond obtained should be formed in a
10
Projets de recherche
Benoit Daoust
stereocontrolled way (1). Coupling of this reaction with other transformations in order to produce onepot procedures will be evaluated. For example, Claisen rearrangement of -oxy enamides prepared by
this original methodology should produce N-acylated amino acids stereoselectively in a one-pot
procedure (see Scheme 4).
X
R
N
ZCONRX
O
X
In
N
R1 R
10
R1
9
COZ
O
O
COZ
R1
11
Scheme 4
Impact : These studies will provide fundamental information on the reactivity of ynol ethers in chainradical 1,2-additions, on the regioselectivity and stereoselectivity of these additions, and on the
influence of steric and electronic effects on both the reactivity and stereoselectivity. It will also provide
new tools to synthesize enol ethers, -halo enol ethers and N-acylated amino acids in a
stereocontrolled way.
2. Electrochemistry of ynol ethers
Context : Anodic oxidation is a mild, selective, and non-polluting method for the oxidation of organic
compounds. A number of authors have shown that electron-rich enol ethers can be oxidized selectively
in the presence of certain functional groups under controlled potential conditions to form C-C bonds in
high yield (10). However, to the best of our knowledge, the study of the electrochemical behaviour of
ynol ethers have not been reported so far.
Objective : We will examine the electrochemical behaviour of ynol ethers in order to see if their anodic
oxidation can be used to trigger the mild formation of inter and intramolecular C-C bonds, leading to
the construction of a wide variety of substituted enol ethers, diesters and quinones.
RO
-eMeOH
12
O
RO
RO
R'
R'
O
R'
RO
Scheme 5
OR
OMe
13
H+, H2O MeO
OR
R'
15
R'
MeO
-eMeOH
OMe R'
R' MeO
OR
OMe
14
Methodology : We will investigate the voltammetric and coulometric behaviour of ynol ethers in
different media in order to determine their oxidation potential, the lifetime of the intermediate radical
cations, the reactivity of the radical cation-ynol ether pair in the C-C bond formation and the number
of electron exchanged in the process. The coulometric studies will be coupled with preparative
electrooxidations and isolation and characterization of the products formed. For example, anodic
oxidation of ynol ether 12 in methanol should lead to the conjugated bis-ketene ketal 13 (see Scheme
5). The latter should be more easily oxidized than 12 and therefore should be immediately oxidized
further to diortho ester 14, the hydrolysis of which would afford the fumarate 15. The intramolecular
version of this reaction will be studied (Scheme 6).
11
Projets de recherche
Benoit Daoust
OR
OR
-eMeOH
2) H+, H2O
R'
17
16a R' = Ar
16b R' = OR''
CO2H
1) -e-, MeOH
OMe
R'
COZ
18a Z = Ar
18b Z = OH
OMe
MeO
OR
Z
Z
MeO
Scheme 6
R'
19
Z = COR, CN, SO2R, NO2
Anodic oxidation of 16 should produce, via the easily oxidized diene 17, cyclic compound 18. We will
look at the possibility of trapping cisoid diene 17 in situ, before further oxidation, in a Diels-Alder
reaction with an electroinactive electron-poor dienophile to give diketal 19 which should be more
difficult to oxidize than ynol ether 16 and could be isolated. Such compounds 19 are precursors to a
variety of quinones. Note that the same trapping with diene 13 is impossible since none of 13 is in its
cisoid form due to steric constraints. Consequently, no Diels-Alder reaction is possible in this case. On
a longer term, these electrochemical tools will be applied to syntheses of natural products (see LongTerm Objectives).
Impact : This project will provide, for the first time, information on how ynol ethers behave towards
anodic oxidation. It should also lead to the development of environmentally and friendly synthetic
tools using easily prepared starting materials.
3. Ionic cyclization of ynol ethers
Context : The use of ynol ethers in ionic chemistry is known (11-14). Fundamental studies revealed
that an ynol ether, in the presence of an electrophile produces a cationic ketene (15). In aqueous or
alcoholic medium, this extremely powerful electrophile is hydrolyzed to the ester. These studies also
established that the addition of electrophiles to ethynyl ethers takes place with the attachment of the
electrophilic component of the reagent to the more electron rich -carbon atom of the triple bond (15).
To our knowledge, no studies of reaction of ynol ethers with electrophiles in non-nucleophilic media
have been reported.
Objective : Reactions of ynol ethers with electrophiles in non-nucleophilic media will be studied. The
purpose is to understand the reactivity of ynol ether derived cationic ketene intermediates with
strategically placed internal nucleophiles and to develop useful synthetic transformations.
Br
R
R
R
O
O
OH
( )n
-
1) SmI2
1) H , TCE
( )n 2) RLi, H O
2
2) aq. NaHCO3
22
21
20
R = H, alkyl
( )n
Scheme 7
E
E
E
R
22
R
R
-H+
( )n
( )n
23
24
Scheme 8
12
O
O
+
O
E+
( )n
25
Projets de recherche
Benoit Daoust
Methodology : We will synthesized models such as 22 and 27 (see Schemes 7 and 9). The synthesis of
compound 22 will begin with the reaction of ketone 20 with samarium iodide (16). The resulting
alcohol 21 will then be transformed to ynol ether 22 following Greene's protocol (17). Similarly, ynol
ether 27 (Scheme 9) will be prepared by reacting alcohol 26, prepared by Danheiser's method (18),
with trichloroethylene (TCE) in basic medium (17). Reaction of 22 with an electrophile should give
cationic ketene 23 (Scheme 8). In a non-nucleophilic medium, 23 might undergo a [1,3] sigmatropic
rearrangement (suprafacial with inversion of configuration at the migrating carbon) to afford 24 after
deprotonation. In situ aromatization should lead to highly substituted 2,3-annulated furan 25.
Similarly, cyclopropyl ynol ether 27 (Scheme 9) would give the 3,4-annulated furan 30.
OH
( )n
26
1) H-, TCE
O
2) RLi, H2O
( )n
E+
27
-H+
O
O+
O+
( )n
( )n
( )n
30
29
E
E
28
E
Scheme 9
2,3 and 3,4-fused furans are encountered in a variety of natural products (19) and are advanced
intermediates in the formation of important synthetic targets such as angular triquinanes (20a) and
highly functionalized medium ring ethers (20b). An heterogeneous solid acid such as montmorillonite
K10 or Amberlyst should constitute a non-nucleophilic medium of choice since such solid acids have
been shown to efficiently form highly reactive cations that subsequently performed intramolecular
addition prior to hydrolysis (21). Furthermore, those solid acids are environmentally friendly since
they are non volatile, easily recovered and reusable. This new method using mild solid acids should be
attracting as most existing furan syntheses employ strong acid (22).
Impact : These studies will lead to a better understanding on how cationic ketene species are formed,
how their reactivity can be controlled and how they can be used as interesting and versatile synthetic
tools for the formation of furanoterpenes in smooth conditions.
LONG-TERM OBJECTIVES
With the understanding gained on the stereochemical outcome and kinetics of electrophilic radical
addition and ionic chemistry involving ynol ethers, we will attempt the construction of highly
functionalized carbon moities that include quinones, exocyclic enol ethers and substituted furans. For
example, the method developed in the discussed proposal for producing substituted fused furan
synthons will be used to prepare furocoumarins like pterophyllins 2 and 4 (23). Other methods
available for the synthesis of furocoumarins have found their synthetic exploitation limited by the
difficulties in controlling regiochemistry of the linear and angular adduct. Our technique should be
experimentally simple and highly regioselective. We also envisaged to make use of ynol ether radical
cyclization for the construction of angular triquinanes skeleton (e.g. 33) (Scheme 10) and
functionalized bicyclo[3.2.1]octanes (36) (Scheme 11).
O
Et3B
RO2C
X
RO
31
RO2C
RO
X
32
Scheme 10
13
H
33
Projets de recherche
Benoit Daoust
O
O
O
R1
Br, I
O
34
R1
R1
R2
R2
OH
35
RO
R2
RO
OH
Br, I
36
Scheme 11
The electrochemical tools developed will be applied to the construction of functionalized quinones like
37, an antibiotic of the isolactarane family. The knowledge developed in the present research projects
will be used to study the radical addition of other heteroatomic substituted acetylenes like ynamines
and thioacetylenes towards haloalkanes. We also plan to study the unexplored electrochemical
behaviour of these nucleophilic species.
O
CHO
37
O
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Projets de recherche
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