Key words ynamines - ynamides -
N -alkynyl heterocycles - amination - copper catalysis - alkynes
Introduction: The ABC of Ynamides
1
Introduction: The ABC of Ynamides
While the first attempted preparation of nitrogen-substituted alkynes, ynamines, can
be traced back to 1892,[
1
] these most valuable building blocks were only isolated in 1958.[
2
] Serendipity, which is often cited as a key factor in making scientific discoveries,
played a crucial role in this early breakthrough by Zaugg, Swett, and Stone at Abbott
who reported an ‘unusual reaction of propargyl bromide’. As mentioned in their publication,
‘when an attempt to alkylate phenothiazine 1 with propargyl bromide failed using the customary conditions of sodamide in xylene,
the procedure was changed to one using sodium hydride in dimethylformamide. Under
these conditions, alkylation occurred to give a 70% yield of product which turned
out to be N -(l-propyny1)phenothiazine 2 instead of the desired isomeric N -(2-propynyl)phenothiazine’ (Scheme [1 ]). Forty-eight grams of this product could be isolated and an ynamine was characterized
for the first time.
Gwilherm Evano (left) was born in 1977 and studied chemistry at the Ecole Normale Supérieure in
Paris and received his Ph.D. from the Université Pierre et Marie Curie in 2002 under
the supervision of Profs. François Couty and Claude Agami. After postdoctoral studies
with Prof. James S. Panek at Boston University, he joined the CNRS as Chargé de Recherche
at the University of Versailles in 2004. He then moved to the Université Libre de
Bruxelles as Associate Professor in 2012. He was a recipient of the Award for vocation
in Medicinal Society of the French Medicinal Society, the CNRS bronze medal, a Thieme
Journal award, and the Acros Prize in organic chemistry of the French Chemical Society.
He has coauthored 65 publications and 10 book chapters with research interests in
developing copper-mediated transformations and the chemistry of heteroatom-substituted
alkynes as well as the total synthesis of natural and/or biologically relevant products.
Kévin Jouvin (middle) was born in 1985 and studied chemistry at the University Joseph Fourier
in Grenoble (France) where he did his undergraduate research with Dr. Demeunynck.
He then joined the group of Gwilherm Evano in Versailles where his work focused on
the development of new syntheses of heteroatom-substituted alkynes and on the development
of copper-catalyzed transformations. He obtained his Ph.D. degree in October 2012
and joined the group of Prof. Alois Fürstner at the Max-Planck-Institut für Kohlenforschung
as a postdoctoral fellow in November 2012.
Alexis Coste (right) was born in 1982 and studied chemistry at the Ecole Supérieure de Chimie
Organique et Minérale. After undergraduate research with Profs. Lubin-Germain and
Augé at the University of Cergy-Pontoise, he moved to the University of Versailles
as a National Cancer Institute Fellow where his worked focused on the development
of new copper-mediated transformations, including the synthesis of ynamides, and on
natural product synthesis under the supervision of Gwilherm Evano. He obtained his
Ph.D. degree in 2010 and since then he has been a postdoctoral research fellow at
the Massachusetts Institute of Technology in the group of Prof. Mohammad Movassaghi.
Scheme 1 The first synthesis of an ynamine (1958)
The synthetic potential of these nitrogen-substituted alkynes then became quickly
apparent and their reactivity was extensively explored in the 1960s and 1970s, the
great advantage of these building blocks being their high reactivity due to the polarizing
effect of the nitrogen on the alkyne.[
3
] This high reactivity was, however, also found to be a major limitation to the further
extension of their use in organic synthesis. Ynamines are indeed readily hydrolyzed
to the corresponding amides, which renders their preparation and handling difficult;
their toxicity is an additional factor.
In sharp contrast, ynamides 3 , compounds in which the donating ability of the nitrogen is diminished by the presence
of an electron-withdrawing group on this atom, are less prone to hydrolysis and display
an excellent balance between stability and reactivity.[
4
] They can indeed, at least in most cases, be stored for years without degradation
and are easily handled and purified using standard techniques. These compounds, which
were actually introduced in 1972 by Viehe,[
5
] include a whole range of nitrogen-substituted alkynes such as N -alkynyl-amides or N -alkynyl-lactams 4 , N -alkynyl-carbamates or N -alkynyl-oxazolidinones 5 , N -alkynyl-sulfonamides or N -alkynyl-sultams 6 , N -alkynyl-ureas or N -alkynyl-imidazolidinones 7 , N -alkynyl-imides (ynimides) 8 , N -phosphoryl-ynamines 9 , and N -alkynyl-hydrazides 10 (Figure [1 ]). Besides these compounds, other electron-deficient ynamines have recently emerged
such as N -alkynyl-conjugated heterocycles 11 and N -alkynyl-imines 12 (ynimines) that share with ynamides the same balance between stability and reactivity.
The stability of these ynamides provided by the presence of the electron-withdrawing
group, which can also act as a chiral auxiliary or a directing group, make them ideal
candidates for the design of new and original transformations. Indeed, their outstanding
characteristics and the development of general methods for their synthesis have attracted
the attention of an ever increasing number of research groups and an impressive array
of new, efficient, selective, and remarkably elegant reactions have been developed
from these building blocks over the past decade. A simple glance at the exponential
evolution of the number of publications per year on the chemistry of ynamides is quite
astounding and the ‘ynamide boom’ we mentioned in our 2010 review is definitely happening
(Figure [2 ]).[4a ]
[6 ]
[7 ]
Figure 1 Ynamides and related nitrogen-substituted alkynes
The emergence of ynamides as a ‘modern functional group for the new millennium’ , as nicely stated in Richard Hsung’s review,[
4b
] is strongly related to the recent development of robust methods for their synthesis.
These processes, based on various amination strategies, have replaced older procedures
and most classes of ynamides are now readily available from various precursors, even
on a multigram scale. These methods will be described in this short review, after
a brief presentation of the more classical syntheses (section 2), and they have been
classified according to the alkynylating agent used for the formation of the Csp–N
bond (sections 3–7).
Figure 2 Ynamide publications and citations per year – the ‘ynamide boom’ (source: Web of Science® , November 22 2012)
Synthesis of Ynamides at the Dawn of the 21st Century: Elimination and Isomerization
2
Synthesis of Ynamides at the Dawn of the 21st Century: Elimination and Isomerization
As mentioned in the introduction, the first synthesis of an ynamide was reported in
1972 by Viehe, some fourteen years after the first isolation of a nitrogen-substituted
alkyne by Zaugg and co-workers. The synthesis of yne-urea 15 was based on the base-induced elimination of the corresponding α-chloroenamide 14 , itself obtained from reaction of N -methyl-2-phenylacetamide (13 ) with an excess of Viehe’s salt followed by hydrolysis (Scheme [2 ]).[
5
]
Scheme 2 The first synthesis of an ynamide (1972)
This result set the standard for the synthesis of ynamides for the next thirty years
or so, their preparation by elimination from the corresponding halo-enamides being
the method commonly used up to 2003. In 2001, the Hsung group extended this procedure
to the use of β-bromoenamides 17 , compounds readily obtained by bromination of enamides 16 with bromine or N -bromosuccinimide.[
8
] As in the Viehe’s synthesis, potassium tert -butoxide was used for the elimination step, the major limitation being the absence
of reactivity of the E -isomers of the starting β-bromoenamides 17 towards the key elimination (Scheme [3 ], eq 1). Besides α-chloro- and β-bromoenamides [as well as β-(trifluoromethylsulfonyloxy)enamides[
9
]], β,β-dichloroenamides 18 , easily obtained by treatment of formamides with triphenylphosphine and tetrachloromethane,
were also found to be suitable substrates for the preparation of ynamides based on
an elimination strategy, this step being involved prior substitution of the second
chloride by chloride/lithium exchange[
10
] or after Suzuki–Miyaura cross-coupling[
11
] (Scheme [3 ], eq 2 and 3). It should be noted that α,β-dichloroenamides have also been used in
related processes for the synthesis of N -alkynyl-imidazoles.[
12
]
Scheme 3 Synthesis of ynamides based on elimination from halo-enamides
Besides these routes to ynamides based on an elimination step from the corresponding
halo-enamides that were developed on the basis of Viehe’s original synthesis, the
Zaugg procedure based on isomerization of propargylamines was also revisited. It
was found to be a convenient route to nitrogen-substituted alkynes, at least before
the emergence of more straightforward syntheses based on direct amination reactions.
Indeed, the Hsung group extensively studied this transformation which was found to
be rather efficient for the synthesis of yne-amides 22 (Scheme [4 ]),[
13
] the isomerization of other substrates such as N -propargyl-carbamates being less efficient.[
8
]
Scheme 4 Synthesis of ynamides based on isomerization of N -propargylamides
These two main routes for the preparation of ynamides combined with the palladium-
or copper-catalyzed functionalization of terminal ynamides[10b ]
[e ]
[14 ] and the use of alkynyliodonium salts (vide infra ) set the foundations of their chemistry. However, only a limited number of research
groups were actually involved in this research area up to 2003, the preparation of
the starting building blocks remaining a barrier to unleashing the full potential
of ynamides. This situation has been resolved over the last ten years with the development
of general, robust, and efficient methods for the preparation of these nitrogen-substituted
alkynes which has had a dramatic impact on their chemistry, at least one paper on
this topic is published every single week. While all syntheses of ynamides described
so far rely on the formation of the triple bond, by elimination or isomerization,
after formation of the C–N bond, robust and more straightforward ynamide syntheses
have been recently developed based on cross-coupling between an alkynylating agent
and a nitrogen nucleophile or electrophile and these allow the formation of the N–C≡C
motif in a single operation. An overview of these methods will be given in sections
3–7, the methods have been classified according to the nature of both reaction partners,
starting with the amination of acetylenic derivatives involving hypervalent iodonium
salts.
Synthesis of Ynamides by Amination of/with Hypervalent Iodonium Salts
3
Synthesis of Ynamides by Amination of/with Hypervalent Iodonium Salts
An interesting entry to ynamides, which also contributed to the revitalization of
their chemistry, consists of the use of alkynyliodonium triflates,[
15
] as originally described by Stang in 1994 for the preparation of push–pull ynamines.[
16
] Upon reaction with lithium diphenylamide (23 ), alkynyl(phenyl)iodonium triflates 24 substituted with electron-withdrawing or trimethylsilyl groups were shown to smoothly
transfer their alkynyl moiety, yielding stabilized ynamines 25 in moderate to good yields (Scheme [5 ], eq 1). Capitalizing on this result, this reaction was next extensively used for
the preparation of a wide range of ynamides 3 with various efficiencies (Scheme [5 ], eq 2), notably by the groups of Witulski, Feldman, and Rainier,[
17
] and extended to the preparation of several N -alkynyl heterocycles.[
18
] It should be noted that the use of a strong base such as BuLi or KHMDS is not strictly
required with sulfonamides since the use of cesium carbonate was shown to be equally
efficient in some cases.[
19
]
Scheme 5 Synthesis of push–pull ynamines and ynamides by amination of alkynyliodonium triflates
with metalated N-nucleophiles
Although this reaction has proven to be rather useful, it requires in most cases the
formation of the metalated N-nucleophile by reaction with a strong base such as BuLi
or KHMDS and is limited by the poor availability of the starting iodonium salt, which
can be substituted only by a proton or silyl, aromatic, or electron-withdrawing groups.
In fact, the major advantages of this procedure are its utility for aminations involving
acyclic secondary amides or other N-nucleophiles performing poorly in copper-mediated
processes (such as acyclic secondary amides or bulky nucleophiles), the corresponding
ynamides being rather difficult to prepare in good yields by other methods.
An especially interesting alternative was reported in 2012 by the Muñiz group. They
developed an efficient metal-free direct amination of alkynes with bis(sulfonyl)amine-derived
aryliodonium acetates 27 (Scheme [6 ]). These reagents, readily prepared by reaction of the corresponding bis(sulfonyl)amines
with iodosobenzene diacetate, were shown to react smoothly with terminal aromatic
alkynes 28 in 1,2-dichloroethane at 80 °C to give the corresponding aryl-substituted ynamides
29 in good yields and short reaction times. This reaction, therefore, represents a very
useful alternative to the use of alkynyliodonium triflates, although the reactivity
of other alkynes and other N-nucleophiles has not been reported.[
20
]
Scheme 6 Synthesis of ynamides by metal-free direct amination of alkynes with bis(sulfonyl)amine-derived
aryliodonium acetates
The proposed mechanism for the formation of ynamides 3 from alkynyliodonium triflates 24 is shown in Scheme [7 ]. It would first involve nucleophilic addition of the metalated N-nucleophile 26 β to the iodine in 24 followed by a 1,2-shift from the resulting vinylcarbene 30 to form ynamide 3 . The intermediacy of an alkynyliodonium salt was proposed to account for the formation
of ynamides from bis(sulfonyl)amine-derived aryliodonium acetates 27 , the former being formed by dissociation of the latter followed by reversible coordination
of the electrophilic iodine(III) to the alkyne yielding 31 and loss of acetic acid by internal deprotonation of the acidified C–H bond in 31 .
Scheme 7 Proposed mechanism for the formation of ynamides from alkynyliodonium triflates and
bis(sulfonyl)amine-derived aryliodonium acetates
In addition to these routes, which provide interesting entries to ynamides especially
with poor nucleophiles in the first case and for the preparation of aryl-substituted
N ,N -bis(sulfonyl)ynamines in the second, major advances in the chemistry of ynamides
have been made since 2003 by the use of copper-mediated cross-coupling reactions.
General and robust procedures have been developed using copper catalysis for the amination
of an impressive range of acetylenic reagents or synthetic equivalents. These syntheses
and their scope and limitations will be discussed in sections 4 and 5 of this short
review.
The Emergence of General Syntheses of Ynamides: Copper-Catalyzed Amination of Bromoalkynes,
gem -Dibromoalkenes, and Alkynyl(triaryl)bismuthonium Tetrafluoroborates
4
The Emergence of General Syntheses of Ynamides: Copper-Catalyzed Amination of Bromoalkynes,
gem -Dibromoalkenes, and Alkynyl(triaryl)bismuthonium Tetrafluoroborates
As already mentioned, the renaissance of copper-catalysis[
21
] and the remarkable work from the Buchwald group for the development of mild Ullmann–Goldberg-type
cross-coupling reactions[
22
] had a deep impact on the chemistry of ynamides. Indeed, inspired by early results
from the Buchwald group, Hsung and co-workers reported in early 2003 a straightforward
method for their preparation. Using a combination of copper(I) cyanide, N ,N ′-dimethylethylenediamine, and potassium phosphate in refluxing toluene, they demonstrated
that alkynyl bromides 32 could be readily aminated with oxazolidinones, cyclic secondary amides, and carbamates
33 to give the corresponding ynamides 3 in moderate to good yields (Scheme [8 ], eq 1).[
23
] While these results represented a significant breakthrough, the substrate scope
was, however, quite narrow, low yields being obtained with most amides, and the reaction
being inefficient with sulfonamides. A related procedure was published almost simultaneously
by the Danheiser group who reported that the amination of bromoalkynes 32 could be performed at room temperature provided that the N-nucleophiles were deprotonated
with KHMDS prior to cross coupling and that stoichiometric amounts of copper(I) iodide
in pyridine were used (Scheme [8 ], eq 2).[
24
] Using these conditions, carbamates, oxazolidinones, imidazolidinones, and sulfonamides
were successfully transformed into the corresponding ynamides 3 in good yields.
Scheme 8 Synthesis of ynamides by copper-mediated amination of alkynyl bromides: the first
developments. Hsung’s 1st generation (eq 1) and Danheiser’s procedure (eq 2).
A more general procedure, probably one of the best routes to ynamides to date, was
next published in 2004 by the Hsung group who reoptimized its catalytic system in
order to broaden the scope of their amination. The combination of copper(II) sulfate
pentahydrate and 1,10-phenanthroline was found to be especially efficient for the
amination of bromoalkynes 32 with most classes of nitrogen nucleophile 33 (carbamates, oxazolidinones, lactams, acyclic secondary amides, imidazolidinones,
and sulfonamides) with remarkable efficiency (Scheme [9 ]).[
25
] This procedure, which was also performed intramolecularly, was later on extended
to other nitrogen nucleophiles such as bulky carbamates,[
26
] phosphoramidates,[
27
] diethylamine (although the intermediate ynamines could not be isolated and dimerized
to the corresponding naphthalene-1,3-diamine)[
28
] and various π-excessive nitrogen heterocycles (imidazoles, benzimidazoles, pyrazoles,
indazoles)[
29
] using slight modifications of Hsung’s system. As an important note, the origin of
potassium phosphate is crucial for the success of the reaction, the presence of hydrates
providing lower yields of ynamides.[
30
] It should also be mentioned that iron(III) chloride was also reported to be an efficient
catalyst for the exact same transformation,[
31
] although no control experiments to determine the role of copper impurities in iron
salts, which were recently shown to be crucial in related processes,[
32
] were performed.
Scheme 9 Synthesis of ynamides by copper-catalyzed amination of alkynyl bromides: Hsung’s
2nd generation procedure
The use of the direct amination of bromoalkynes with N-nucleophiles provided the sought-after
general and straightforward entry to ynamides. This procedure is, however, not universal,
the synthesis of electron-rich aromatic bromoalkynes being problematic in some cases
and the preparation of alkyl-substituted ones being quite painful due to their volatility
and lachrymatory properties. Alternative reagents were, therefore, needed and we
introduced gem -dibromoalkenes 34
[
33
] as cross-coupling partners in 2009. These compounds, which are readily prepared
by the Ramirez olefination or the more practical Lautens modification from the corresponding
aldehydes,[
34
] were shown to be efficient reagents for the synthesis of a wide range of ynamides
from sulfonamides, oxazolidinones, carbamates, and lactams (Scheme [10 ]).[
35
] The choice of the base and solvent turned out to be crucial for this transformation
to avoid the competitive formation of diynes,[
36
] ketene N ,N -acetals,[
37
] or α-bromoenamides.[
35c
] The combination of cesium carbonate and dioxane or DMF was found to be optimal and
provided the desired ynamides in good yields, even on complex substrates. We next
extended this procedure to benzimidazoles and indazoles,[
38
] a reaction where TMEDA instead of the N ,N ′-dimethylethylenediamine ligand we used in our original procedure was found to be
quite efficient[
39
] and which could be also performed with the preformed complex [Cu(phen)PPh3 Br] with improved efficiency.[
40
] As a note, 1,2-dibromostyrenes were also shown to be suitable reaction partners
for the cross coupling with sulfonamides, which might provide an alternative entry
to N -sulfonyl-ynamines, although the synthesis of these reagents is less trivial than
the preparation of the corresponding gem -dibromides.[
41
]
Scheme 10 Synthesis of ynamides by copper-catalyzed amination of gem -dibromoalkenes
Bromoalkynes and gem -dibromoalkenes have been extensively used for the preparation of ynamides, hundreds
of these building blocks having been made by amination of these reagents. In addition
to these syntheses, the quest for alternative reagents that would be commercially
available and/or whose amination could proceed under milder conditions (ideally at
room temperature and without a base) resulted in the development of alternative routes
to ynamides. In this context, a remarkable synthesis of N -alkynyl-imides (ynimides 8 ), synthetic equivalents of highly labile primary ynamines, was reported in 2011 based
on the amidation of alkynyl(triaryl)bismuthonium tetrafluoroborates 35 .[
42
] These reagents, which are prepared by reaction of the corresponding trifluoroborates
with triaryldifluorobismuth, boron trifluoride–diethyl ether complex, and sodium tetrafluoroborate,
were shown to react readily with five-membered-ring imides 36 in the presence of a catalytic amount of copper(I) bromide and triethylamine in dichloromethane
at –40 °C. The corresponding ynimides 8 were obtained in moderate to good yields along with products resulting from competitive
transfer of one aryl group of the starting bismuthonium salt 35 (Scheme [11 ]). While these reagents require several steps for their preparation, which somehow
reduces their synthetic use, they, however, offer the only general entry to ynimides
available to date.
Scheme 11 Synthesis of ynimides by copper-catalyzed amination of alkynyl(triaryl)bismuthonium
tetrafluoroborates
Other efficient strategies that provide mild and/or practical entries to ynamides
based on copper-catalyzed oxidative cross-coupling reactions[
43
] have been reported recently: an overview is given in section 5.
Alternative Practical and Mild Syntheses of Ynamides: Copper-Catalyzed Oxidative Amination
of Alkynes, Potassium Alkynyltrifluoroborates, and Propiolic Acids
5
Alternative Practical and Mild Syntheses of Ynamides: Copper-Catalyzed Oxidative Amination
of Alkynes, Potassium Alkynyltrifluoroborates, and Propiolic Acids
An attractive synthesis of ynamides based on the direct aerobic amination of alkynes
37 was reported by the Stahl group in 2008. Capitalizing on two early reports from Peterson[
44
] and Balsamo and Domiano,[
45
] they developed an efficient catalytic system based on copper(II) chloride in combination
with pyridine, sodium carbonate, and oxygen as the terminal oxidant in toluene at
70 °C to promote the direct cross-coupling between a wide range of terminal alkynes
37 and oxazolidinones, lactams, imidazolidinones, sulfonamides, and indoles 33 (Scheme [12 ]).[
46
] The corresponding ynamides 3 were obtained in good yields from commercially available precursors, the sole limitation
of this process being the requirement for five equivalents of the N-nucleophile and
the slow addition of the alkyne to minimize its competitive Glaser–Hay oxidative dimerization.
This reaction was later on extended to the use of a recyclable copper carboxylate
metal–organic framework catalyst.[
47
] In addition, the development of heterogeneous processes based on the replacement
of the soluble copper(II) chloride by stoichiometric copper(II) oxide (in combination
with potassium chloride and 4-phenylpyridine)[
48
] or copper(II) hydroxide (in the presence of potassium carbonate, cesium carbonate,
or cesium hydroxide)[
49
] allows overcoming the requirement for the slow addition of the alkyne and a reduction
in the amount of the N-nucleophile to two or three equivalents. The scope of the oxidative
amination was, however, not fully examined in the first case since only aromatic alkynes
were used in the study.
Scheme 12 Synthesis of ynamides by copper-catalyzed oxidative amination of terminal alkynes
In an effort to develop an efficient entry to ynimines, interesting variants of ynamines
whose use remains rather limited, mostly due to the difficulties associated with their
preparation, we screened various reagents and conditions for the direct alkynylation
of imines. We eventually found that the Stahl procedure was the only efficient one,
a wide range of terminal alkynes 37 being readily aminated with diarylimines 38 to give the corresponding ynimines 39 in fair to good yields (Scheme [13 ]). This provided the first general synthesis of ynimines, although restricted to
the use of diarylimines as starting materials, the replacement of one aryl group by
an alkyl chain resulting in extensive degradation of both the starting imine and the
resulting ynimine.[
50
]
Scheme 13 Synthesis of ynimines by copper-catalyzed oxidative amination of terminal alkynes
with diarylimines
While the direct amination of alkynes provided a practical entry to ynamides from
commercially available starting materials, this procedure, as those previously described,
still required the use of a base and/or elevated temperature, which can be a strong
limitation for the preparation of sensitive ynamides, a problem we faced in various
projects. A logical evolution of the ynamide synthesis that might allow these limitations
to be circumvented would be to extend the Chan–Lam–Evans coupling involving aryl-
or vinylboronic acids,[
51
] which typically proceed under mild conditions, to their acetylenic analogues. If
we were at first surprised to note that alkynylboronic acids had not been reported,[
52
] we quickly realized why, since all attempts to isolate these reagents resulted in
extensive degradation or, in the best case, protodeborylation. We therefore decided
to switch to potassium alkynyltrifluoroborates 40 ,[
53
] perfectly stable crystalline compounds that are readily prepared from the corresponding
alkynes, and demonstrated that they were readily cross-coupled to a wide range of
N-nucleophiles 33 including oxazolidinones, imidazolidinones, and sulfonamides (lactams gave lower
yields) in good yields (Scheme [14 ]).[
54
] The reaction proceeded smoothly at room temperature and in the absence of base using
a combination of copper(II) chloride dihydrate and 1,2-dimethylimidazole together
with 4 Å molecular sieves and oxygen. The solvent was found to be a key parameter
in this reaction and the use of dichloromethane allowed the homocoupling of the starting
potassium alkynyltrifluoroborates 40 to be suppressed by diminishing their solubility (5 × 10–3 mol·L–1 in this solvent). This procedure provided the first base-free, room temperature synthesis
of ynamides, which might be especially attractive for the preparation of sensitive
ynamides or for substrates possessing potentially reactive functional groups such
as halides or unprotected alcohols.
Scheme 14 Room temperature, base-free synthesis of ynamides by copper-catalyzed oxidative amination
of potassium alkynyltrifluoroborates
It was next demonstrated that propiolic acids 41 could also be used for the synthesis of oxazolidinone-, imidazolidinone-, lactam-,
sulfonamide- and indole-derived ynamides 3 by copper(II) chloride catalyzed decarboxylative cross-coupling under ligand-free
conditions (Scheme [15 ]).[
55
] The resulting ynamides were obtained in moderate to good yields and this reaction,
which requires protracted heating at 100 °C for the decarboxylation step, represents
an alternative entry to ynamides provided that the propiolic acids required are readily
available.
Scheme 15 Synthesis of ynamides by copper-mediated decarboxylative and oxidative amination
of propiolic acids
As shown by all of the results described so far in this article, a wide range of procedures
and reagents are available for the preparation of ynamides possessing various substitution
patterns. These developments are clearly at the origin of the extraordinary development
of the chemistry of these building blocks over the last years, most classes of ynamides
being readily prepared by carefully choosing the appropriate procedure.
In continuation of our research program on the chemistry of ynamides, we needed to
prepare, for various projects, large quantities of ynamides. If they can be successfully
synthesized on a multigram scale using the syntheses we developed with gem -dibromoalkenes and potassium alkynyltrifluoroborates or Hsung’s 2nd generation or
Stahl’s procedures, we struggled with some substrates and felt at some point that
an even more practical synthesis would be helpful. This led us to develop a ‘click’
aerobic amination of copper acetylides which will be described in section 6.
‘Click’ Oxidative Amination of Copper Acetylides: A Practical Entry to Ynamides under
Mild Conditions
6
‘Click’ Oxidative Amination of Copper Acetylides: A Practical Entry to Ynamides under
Mild Conditions
As a gross simplification, and although there is still no evidence on the mechanisms
of these reactions, most copper-catalyzed cross-coupling discussed in sections 4 and
5 are thought to proceed via an alkynylamidocopper(III) complex. A fast reductive
elimination would account for the formation of ynamides from this intermediate, which
could be generated, in a rate-determining step, either by oxidative addition (section
4) or by transmetalation/oxidation (section 5). With this basic picture in mind, we
envisioned the possibility of generating such intermediates by oxidation of the corresponding
copper acetylides 42 in the presence of N-nucleophiles, which might allow the development of a practical
synthesis of ynamides under mild conditions.[
56
] These rock-stable, non-reactive alkynylcopper reagents are easily prepared by simple
reaction of the corresponding terminal alkynes with copper iodide either in a mixture
of aqueous ammonia and ethanol or in DMF in the presence of potassium carbonate followed
by filtration. As expected, they were found to smoothly react with oxazolidinones
and lactams under an atmosphere of oxygen by simple activation with one equivalent
of TMEDA (Scheme [16 ], eq 1) at room temperature.[
57
] In terms of scope this procedure is restricted to unhindered lactams and oxazolidinones,
which must be used in excess. The major advantage, however, lies in its operational
simplicity. Indeed, this self-indicating reaction (upon completion, the reaction mixture
turns from a yellow heterogeneous suspension to a blue solution that can be loaded
directly on to a plug of silica gel) is readily performed in most common solvents
(MeCN, CH2 Cl2 , toluene, THF, DMF, EtOH, THF–H2 O, or neat), without specific precautions, from copper acetylides 42 that are easily prepared on a multigram scale without purification. This procedure
might not be the most general in terms of scope, but is certainly among the most practical
and can conveniently be applied to the preparation of complex ynamides or for large-scale
ynamide synthesis. This reaction was next extended to the oxidative alkynylation of
imines 43 , in order to overcome the limitations of our first generation procedure (Scheme [13 ]). 1,2-Dimethylimidazole was found to be the best promoter in this case and a wide
range of copper acetylides were smoothly transformed to the corresponding ynimines
44 in good yields (Scheme [16 ], eq 2).[
58
]
Scheme 16 Synthesis of ynamides and ynimines by oxidative amination of copper acetylides
Synthesis of Ynehydrazides by Electrophilic Amination of Lithium Acetylides with Diazodicarboxylates
7
Synthesis of Ynehydrazides by Electrophilic Amination of Lithium Acetylides with Diazodicarboxylates
Finally, an amination procedure that was found to be especially convenient for the
synthesis of ynehydrazides should be mentioned. While this virtually unknown class
of ynamides, which clearly offers various possibilities in organic synthesis, could
not be obtained in decent yields by copper-promoted amination of bromoalkynes with
protected hydrazides, a reversal of the polarities of the reagents was found to be
more successful. Indeed, the Batey group prepared a variety of ynehydrazides 47 in good yields by addition of lithium acetylides 45 to sterically hindered diazodicarboxylates such as di-tert -butyl azodicarboxylate (46 , R2 = t -Bu) and diisopropyl azodicarboxylate (46 , R2 = i -Pr) (Scheme [17 ]).[
59
]
Scheme 17 Synthesis of ynehydrazides by amination of lithium acetylides with diazodicarboxylates
Conclusions and Outlook: Ynamides Synthesis, Where Now?
8
Conclusions and Outlook: Ynamides Synthesis, Where Now?
Continuous progress has been made in the synthesis of ynamides by formation of the
Csp–N bond by various amination strategies over the last ten years. Most classes of
ynamides and related nitrogen-substituted alkynes are now available and the preparation
of multigram quantities of these building blocks is no longer problematic. The development
of these syntheses clearly contributed to the emergence of ynamides in organic synthesis,
remarkable reports being published on a weekly basis showcasing their unique reactivity.
There is no doubt that this trend will continue for years to come, the exceptional
reactivity of ynamides being far from fully exploited and their use in natural product
synthesis and in medicinal chemistry clearly being under-utilized.
Although these tremendous advances have considerably simplified the synthesis of ynamides,
this is, however, not a problem solved. Indeed, the preparation of some classes of
ynamides remains problematic, amination procedures involving substrates such as acyclic
secondary amides or ureas being either highly substrate-dependent or completely inefficient,
which strongly limits their development. New classes of ynamides such as ynehydrazides,
ynimides, N -phosphoryl-ynimines, or ynimines have also recently appeared and further developments
in the chemistry of ynamides will also involve the development of new members within
this family.
In short, ynamides will definitely continue to occupy an important role in organic
synthesis and we hope this short review will motivate other research groups to explore
the reactivity of these unique building blocks. There is clearly exciting chemistry
to be discovered with ynamides: try it, you’ll like it!
