1
Introduction
Organoaluminum reagents have been known for more than 150 years since the first synthesis
of ethylaluminum sesquiiodide by Hallwachs and Schafarik in 1859.[1 ] However, the chemistry of these organometallic species is still mostly restricted
to the fields of olefin polymerization and thin-film fabrication by chemical vapor
deposition techniques.[2 ] The range of applications of organoaluminum reagents is surprisingly limited, especially
if one considers that aluminum, the most abundant metal in the earth’s crust, is produced
at low price (a mole of aluminum is now cheaper than a mole of lithium). Trimethylaluminum
is also a major, widely available inexpensive organometallic compound that can act
not only as a cheap methyl donor, but also as metalating or transmetalating agent
for the synthesis of more elaborated organoaluminum reagents.[3 ]
There are probably a few reasons why organoaluminum reagents are still less frequently
used in organic synthesis than other main group organometallic reagents, such as organolithium
or organomagnesium reagents. One of the limitations is that generally only one of
the 3 C–Al bonds will react in synthetic transformations.[4 ] Furthermore, competitive hydride transfer can occur with substituents bearing an
sp3 -C–H bond β to the sp3 -C–Al bond.[5 ] Finally, the main reason for the rather low popularity of organoaluminum as synthetic
reagents has been highlighted by Eisch in his seminal review on the history of aluminum
chemistry: if ether solvents are essential in the reactivity of organolithium or magnesium reagents,
they dramatically reduce the reactivity of alkylaluminum reagents through the formation
of Lewis acid-base adducts .[6 ] However, these solvents are still generally used for the preparation of organoaluminum
reagents by transmetalation, C–H activation, or direct insertion, leading to organometallic
species with limited reactivity.
Among the large variety of organoaluminum compounds, dimethylalkynylaluminum reagents
(Figure [1 ]) look quite attractive.
Figure 1 General properties of mixed dimethylalkynylaluminum reagents
These species are indeed devoid of the major limitations described above. The three
substituents on aluminum do not bear a C–H bond in the β-position. The greater reactivity
of the sp-C–Al bond compared to that of sp3 -C–Al bond will enable selective transfer of the alkynyl moiety, the methyl group
behaving as a nontransferable moiety. Finally, we were able to propose a new route
to these reagents in non-polar solvents, providing compounds with enhanced reactivity.
In this short review, our goal is to focus on the preparation and reactivity of mixed
dimethylalkynylaluminum reagents with a special focus on their peculiar reactivity
and synthetic utility in selective organic transformations.[7 ]
2
Preparation of Dimethylalkynylaluminum Reagents
A classical way to prepare dialkylalkynylaluminum compounds is by salt metathesis
from the corresponding alkali acetylides (Scheme [1 ]). This is the method of choice starting from terminal acetylenes bearing tert -butyl[8 ] or trialkylsilyl groups,[9 ] or showing weak acidity such as alkoxyacetylenes.[10 ]
Scheme 1 Preparation of dimethylalkynylaluminum reagents by transmetalation
This approach requires a first metalation step, generally conducted at low temperature,
and careful control of the transmetalation experimental conditions to avoid the presence
of residual traces of dialkylaluminum halides. The equivalent of lithium or sodium
chloride produced in the second step can be removed by filtration if a non-polar solvent
is used, but can affect the reactivity of the resulting organoaluminum reagents if
the transmetalation step is conducted in Et2 O.
Trimethylaluminum is not sufficiently basic to metalate a terminal alkyne at room
temperature in non-polar solvents. The use of higher temperatures generally leads
to a mixture of compounds resulting from competitive carboalumination side reactions.[11 ] Interestingly, clean metalation occurs at room temperature in triethylamine, as
reported by Binger in 1963.[12 ] This observation led to the development of a base-catalyzed alumination of terminal
alkynes with trimethylaluminum.[13 ] A mechanistic investigation showed that several Lewis bases can catalyze this transformation,
the most efficient being N ,N -bis(trimethylsilyl)methylamine (Scheme [2 ]).[14 ] Using this base, clean terminal alumination can be obtained at room temperature
with only 1 or 2 mol% of the catalyst. In 2018, the use of zwitterionic neodymium(III)
heterobimetallic compounds was reported to catalyze a similar reaction.[15 ]
Scheme 2 Preparation of dimethylalkynylaluminum reagents by base-catalyzed terminal alumination
Dimethylalkynylaluminum reagents are typically prepared by simply adding MeN(SiMe3 )2 and the alkyne to a 2 M commercial solution of AlMe3 , leading to a stable 1.6 M solution of the organometallic reagent. The prepared air-
and moisture sensitive organoaluminum solutions can be stored under argon in the dark
for several days at room temperature. Although commercially available heptane or toluene
solutions can both be used indiscriminately, dimethyl(phenylethynyl)aluminum tends
to crystalize in alkanes and is better prepared in toluene.
An alternative to this batch procedure based on flow chemistry has also been proposed.
In this case, a resin-supported tertiary amine is used to promote the metalation step.
This procedure delivers dimethylalkynylaluminum reagents without any residual traces
of the catalyst with an increased reaction rate (Scheme [2 ]).[16 ]
3
Reactivity of Dimethylalkynylaluminum Reagents
Alkynylaluminum reagents exhibit a rather low nucleophilic character. This reactivity
can be explained by the low ionic character of the C–Al bond, and their bridged dimeric
nature in non-coordinating solvents. As a result, most of the reactions involving
the carbon–metal bond will be triggered by the complexation of the acidic aluminum
center to the substrate, leading to activation of the nucleophile. As a consequence,
the nature of the solvent will play a major role in the reactivity of dimethylalkynylaluminum
reagents. This typical behavior is perfectly illustrated in the reaction with chiral
oxazolopiperidines (Scheme [3 ]). These polyfunctional compounds are known to react with organolithium, -cuprates,[17 ] or -magnesium reagents[18 ] at their amino-nitrile moiety. Dimethylalkynylaluminum reagents react, in a complementary
manner, selectively with the oxazolidine motif by coordinating the most Lewis basic
part of the substrate; diastereoselective alkynylation, without methyl transfer, is
obtained.[14 ] The reaction proceeds at 0 °C in toluene. No reaction occurs if THF is used as a
cosolvent, highlighting the role of coordination in this transformation.
Scheme 3 Example of a selective Lewis acidity triggered reaction of dimethylalkynylaluminum
reagents
3.1
Reactions with Csp3 Electrophiles
3.1.1
Alkyl Halides
The reaction of dimethylalkynylaluminum reagents with alkyl halides takes place through
a dissociative pathway and involves the coordination of the metal center to the leaving
group. The exceeding high affinity of aluminum for fluorine (663 kJ mol–1 ) has been exploited for the selective alkynylation of tertiary alkyl fluorides (Scheme
[4 ]).[19 ] Interestingly, no reaction was observed using the corresponding chloro analogues.
Scheme 4 Nucleophilic substitutions of alkyl fluorides
3.1.2
Propargylic Sulfonates
The Lewis base activation of dimethylalkynylaluminum reagents associated with their
low basicity has been exploited in a very elegant synthesis of skipped diynes from
propargylic electrophiles (Scheme [5 ]).[20 ] The coordination of the metallic nucleophile to the electrophile drives a clean
SN 2 reaction and avoids an undesired SN 2′ substitution at the triple bond. Particularly noteworthy is the reaction of terminal
propargylic sulfonates, known to generally react predominately on the least substituted
carbon and lead to allene intermediates. The corresponding chloro or iodo derivatives
do not react under similar reaction conditions. A six-membered aluminum-coordinated
transition state has been proposed to explain this difference in reactivity.
Scheme 5 Selective synthesis of skipped diynes
3.1.3
Thioacetals
Sulfones are excellent leaving groups for the synthesis of medium-sized α-substituted
cyclic ethers; the nucleophilic substitution involves a reactive oxonium intermediate.
Interestingly, thioacetals are selectively activated in the presence of acetals (Scheme
[6 ]).[21 ]
Scheme 6 Alkynylation of lactone-derived sulfones
Such selective alkynylation was exploited in the synthesis of the C15–C38 fragment
of okadaic acid (Scheme [7 ]).[22 ] This example is particularly illustrative of the great functional group tolerance
of organoaluminum species as well as their excellent chemoselectivity.
Scheme 7 Selective alkynylation as a key step in the synthesis of the C15–C38 fragment of
okadaic acid
3.1.4
Hemiaminals
Like oxoniums, iminium precursors such as hemiaminals can react with dimethylalkynylaluminum
reagents in a similar manner. This reactivity enables a simple access to various substituted
propargylamines (Scheme [8 ]).[23 ]
Scheme 8 Synthesis of mono- and bis-propargylamines
3.1.5
β-Lactones
Alkynylaluminum compounds are excellent partners in alkyne-propanoic acid homologation
reactions based on the regioselective ring opening of β-propiolactone.[24 ] This reaction was used as a key step in the synthesis of unsaturated fatty acids
(Scheme [9 ]); the same reaction with the corresponding organolithium was unsuccessful.[25 ]
Scheme 9 Homologation of alkynes with β-propiolactone
3.1.6
Epoxides
Epoxides react readily with dimethylalkynylaluminum reagents (Scheme [10 ]).[26 ] As expected, the ring opening is generally fully regioselective with terminal epoxides,
the least substituted carbon being the most reactive one.
Scheme 10 Regioselective epoxide opening by dimethylalkynylaluminum reagents
The regioselectivity of the reaction is less pronounced with internal epoxides. It
can however be controlled by neighboring coordination groups. This effect has been
beautifully illustrated with fluorine-substituted substrates (Scheme [11 ]). Thus, a β-fluorinated epoxide (X = F) reacted in less than 10 minutes at –78 °C
to give a homopropargyl alcohol I in a fully regioselective manner and 70% chemical yield. In marked contrast, the
corresponding non-fluorinated substrate (X = H) was less reactive, delivering an almost
equimolar mixture of isomers I /II in only 40% yield. This fluorine assistance can be explained by the high affinity
of aluminum to fluorine, leading to the formation of a transient pentacoordinate complex
that delivers its alkynyl group in a regioselective manner.[27 ]
Scheme 11 Fluorine-assisted epoxide opening
The formation of an acid-base complex prior to the alkynyl group delivery can lead
to interesting rearrangements. The regioselective alkynylation of 2,3-epoxy sulfides[28 ] or selenides[29 ] (Scheme [12 ]) involves an episulfonium or episelenium intermediate. In the case of sulfur derivatives,
the C-2 alkynylation product III was preferentially obtained with a global retention of configuration, whereas alkynylation
occurred at C-1 to give IV starting from the corresponding selenium precursor.
Scheme 12 Alkynylations of 2,3-epoxy sulfides or selenides
Another chemo- and regioselective alkynylation of an epoxide involving a neighboring
group participation can be observed on bicyclic hydrazines (Scheme [13 ]).[30 ] This behavior is a remarkable example of the synthetic potential of strong Lewis
acidic, poor nucleophilic reagents such as organoaluminum compounds.
Scheme 13 Neighboring group participation in bicyclic hydrazine epoxide alkynylation
3.1.7
Aziridines
Dimethylalkynylaluminum compounds react with N -sulfonylaziridines. The reaction has to be conducted in CH2 Cl2 and proceeds via coordination of the organometallic compound to the aziridine-protecting
group with subsequent intramolecular alkynylation.[31 ] Interestingly, a tran s-1,2-disubstituted cyclohexene was obtained from an aziridine-fused cyclohexene whereas
cis -1,4-disubstituted cyclopentene was formed from an aziridine-fused cyclopentene. The
same aziridine reacted with trimethylaluminum to give a cis -1,2-disubstituted cyclopentene (Scheme [14 ]).
Scheme 14 Ring opening of cyclic vinyl aziridines
3.1.8
β-Azido Enol Ethers
β-Azido silyl enol ethers can be ionized by Lewis acids like AlMe3 and generate a reactive enonium that can undergo a conjugate 1,4-addition. This original
reactivity was used to prepare β-alkynyl enol ethers in 70–98% yield (Scheme [15 ]).[32 ]
Scheme 15 Alkynylation of β-azido silyl enol ethers
3.2
Reactions with Csp2 Electrophiles
3.2.1
Carbonyl Compounds
Dimethylalkynylaluminum reagents react readily with carbonyl compounds by selectively
transferring their alkynyl moiety (Scheme [16 ]).[33 ] The general order of reactivity is acyl chlorides > aldehydes > ketones >> esters.
Of particular interest is the reaction with acyl chlorides, which provides a very
simple and convenient access to ynones.[34 ] The use of 1,2-dichloroethane as a solvent is crucial in this transformation since
no reaction occurs in THF. The preparation of symmetrical diynones from oxalyl chloride
is also noteworthy.[34 ]
Scheme 16 Reaction of dimethylalkynylaluminum reagents with carbonyl compounds
3.2.2
Amino Derivatives
The reaction of dimethylalkynylaluminum with nitriles requires a higher temperature
than that used with acyl chlorides, but this is an alternative way to prepare ynones
after hydrolysis of the α,β-alkynylketimine.[35 ] Interestingly, in a one-pot procedure, treatment of the N -(dimethylalumino)-α,β-alkynylketimine addition product with a chloroformate led to
an ynimine carbamate; this straightforward reaction enabled a very efficient access
to 1,2-dihydropyridines via an alkyne isomerization/electrocyclization sequence (Scheme
[17 ]).[36 ]
Scheme 17 Two-step synthesis of disubstituted dihydropyridines from nitriles
Hydroximoyl chlorides and hydrazinoyl chlorides reacted readily with dimethylalkynylaluminum
reagents; the transient aluminate underwent an intramolecular cyclization, leading
to aluminated isoxazoles and pyrazoles. The stability of the C–Al bonds enables this
transformation to be performed at 50 °C without degradation by β-elimination (Scheme
[18 ]). These aluminated heterocycles were then reacted with strong electrophilic reagents
such as isocyanates or N -halosuccinimides.[37 ]
Scheme 18 One-pot, two-step synthesis of trisubstituted oxazoles and pyrazoles
The reaction of dimethylalkynylaluminum compounds with carbohydrate-derived nitrones
was highly stereoselective (Scheme [19 ]);[38 ] cyclization onto the triple bond was not observed. In absence of any other competitive
Lewis basic center, nitrones themselves catalyzed the terminal alumination of alkynes,
leading to a one-pot α-addition from terminal alkynes in the presence of trimethylaluminum.[39 ]
Scheme 19 Reaction of alkynylaluminum reagents with cyclic nitrones
Activated imines, such as N -phosphinoyl[40 ] or N -sulfinylimines,[41 ] react with dimethylalkynylaluminum reagents. Good to excellent diastereoselectivities
were generally obtained when performing the reaction in toluene (Scheme [20 ]). No reaction was observed in THF or diethyl ether, highlighting the importance
of coordination for this transformation.
Scheme 20 Diastereoselective synthesis of propargylamines
The reaction of dimethylalkynylaluminum reagents with diazo(trimethylsilyl)methane
is particularly noteworthy. Instead of attacking the metal center, as classically
described with diazomethane and alkyl-, alkenyl-, or arylaluminum compounds, diazo(trimethylsilyl)methane
behaves as an electrophile with dimethylalkynylaluminum compounds. This unique reactivity
enabled a simple access to α-silylated alkynyl hydrazones.[42 ] These species were readily oxidized into the corresponding diazo derivatives, which
served as useful precursors for geminal bis-propargylsilanes[43 ] or α-silylated propargyl esters (Scheme [21 ]).[44 ]
Scheme 21 Reaction of dimethylalkynylaluminum reagents with diazo(trimethylsilyl)methane and
subsequent transformations
3.2.3
Enones
Dimethylalkynylaluminum reagents add to conjugated enones provided they can adopt
a chelated transition state, leading to an intramolecular delivery of the alkynyl
moiety.[45 ] As a consequence, enones devoid of a proximal coordinating group can undergo a 1,4-addition
only if they are able to adopt a cisoid conformation. This strategy was used for the
two-step synthesis of γ-butyrolactones from a Meldrum’s acid derivative (Scheme [22 ]).[46 ] The low basicity of organoaluminum reagents enabled a clean 1,4-addition whereas
any attempts to add lithium alkynides resulted in nearly quantitative recovery of
starting material, probably because of undesirable γ-deprotonation at the methyl position.
Scheme 22 1,4-Addition to a Meldrum’s acid derivative
The need for a coordinating group in 1,4-addition onto cyclic enones has been exploited
in the diastereoselective desymmetrization of p -quinols by dimethylalkynylaluminum reagents (Scheme [23 ]).[47 ]
Scheme 23 1,4-Addition to p -quinols
4
Transition-Metal-Catalyzed Reactions
4.1
Addition to α,β-Unsaturated Enones
Conjugated addition of dimethylalkynylaluminum reagent to cyclic enones can be quite
challenging due to the lack of a polar directing group allowing the delivery of the
alkynyl group to the enone moiety. This problem can however be circumvented by using
transition-metal-catalyzed reactions. Indeed, the selective 1,4-addition of alkynyl
groups to α,β-unsaturated compounds can be observed in the presence of nickel catalysts
(Scheme [24 ]).[48 ] In this case, an excess of the dimethylaluminum reagent was necessary to prevent
undesired side reaction of the final aluminum enolate with the unreacted enone.
Scheme 24 Nickel-catalyzed 1,4-alkynylations
Interestingly, enantioselective 1,4-additions can be achieved either in the presence
of a Ni(II)–bisoxazolidine catalyst, or using nickel(II) complexes with chiral biphosphine
ligands (Scheme [25 ]). In this last case, the alkynylating species proposed to be a bis(phosphine)nickel
diacetylide, while the dimethylaluminum chloride formed during the metathesis activates
the enone by coordinating to the carbonyl group.[49 ]
Scheme 25 Asymmetric nickel-catalyzed 1,4-alkynylations
4.2
Coupling Reactions
Compared to terminal alkynes or other metallated alkynes, dimethylalkynylaluminum
reagents are rarely used in transition-metal-catalyzed coupling reactions. These compounds
can nonetheless be employed as valuable reagents in palladium-catalyzed cross-couplings
for the selective alkynylation of aromatic halides or triflates (Scheme [26 ]).[50 ] This approach prevents the formation of undesired homodimeric byproducts frequently
observed in Glaser-type reactions.
Scheme 26 Palladium-catalyzed cross-coupling reactions
Dimethylalkynylaluminum reagents can also react with alkynyl bromides in the presence
of nickel(0) catalysts to generate unsymmetrical diynes in good yields (Scheme [27 ]).[51 ]
Scheme 27 Synthesis of unsymmetrical diynes
An interesting palladium-catalyzed coupling between β-tosylvinylsulfoximines and alkynylaluminum
reagents has been reported for the stereospecific synthesis of enynylsulfoximines
(Scheme [28 ]).[52 ]
Scheme 28 Stereospecific synthesis of enynylsulfoximines
5
Triple Bond Reactivity
Although dimethylalkynylaluminum reagents behave mostly as σ-nucleophilic alkynides,
their triple bond can also be engaged in several reactions. This reactivity, combined
with the stability of the C–Al bond, can be exploited in the synthesis of various
organoaluminum compounds. Thus, dimethylalkynylaluminum reagents undergo carbometalation
reactions in the presence of titanium- or zirconium-based catalysts to form geminal
dimetallic species (Scheme [29 ]). Such compounds can also react easily with different electrophiles, such as aldehydes,
ketones, halogens, or acyl chlorides. Remarkably, while for the Al/Ti bismetallic
compound a slow E /Z isomerization can occur at room temperature, the zirconium derivative has proven
to be stereochemically stable.[53 ]
Scheme 29 Methylmetalation of alkynylaluminum reagents
Zirconium-catalyzed reactions can also be used to convert ω-halogenated alkynylaluminum
derivatives into iodocycloalkenes via the formation of cyclic organometallic intermediate
species (Scheme [30 ]).[54 ]
Scheme 30 Intramolecular reaction of bis-metalated reagents
Another remarkable transformation is the copper-catalyzed 3+2 cycloaddition of azides.
This reaction delivered various aluminated triazoles in a regioselective manner. The
new organometallic species were then reacted with various electrophiles (Scheme [31 ]). This synthetic route enables a straightforward access to trisubstituted triazoles.[55 ]
Scheme 31 Copper-catalyzed 3+2 cycloaddition of azides with dimethylalkynylaluminum reagents
and subsequent transformations
6
Conclusion
As shown in this short review, the reactivity of dimethylalkynylaluminum reagents
is, in many aspects, unique and complementary to classical reactivities observed with
polar organometallic reagents. The combination of a metal atom acting as strong Lewis
and a rather stable carbon–metal bond with significant covalent character leads to
interesting regio- and chemoselectivities, which can generally be observed at room
temperature or under refluxing solvent conditions. In all the cases the alkynyl group
is selectively transferred, while the methyl groups remain spectator substituents.
This reactivity, associated with the low price and wide availability of trimethylaluminum,
make these compounds valuable reagents for many synthetic applications.
