Fishing with copper acetylides: Selective alkynylation of heteronucleophiles

Article abstract of DOI:10.1016/j.tet.2018.09.053

Copper acetylides are readily available and especially convenient reagents for the alkynylation of a broad range of heteronucleophiles. Upon simple activation with molecular oxygen in the presence of suitable ligands and solvents, they readily transfer th

Full text of DOI:10.1016/j.tet.2018.09.053

Accepted Manuscript
Fishing with copper acetylides: Selective alkynylation of heteronucleophiles
Céline Guissart, Michel Luhmer, Gwilherm Evano
PII:
S0040-4020(18)31164-5
10.1016/j.tet.2018.09.053
TET 29825
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 September 2018
Accepted Date: 28 September 2018
Please cite this article as: Guissart Cé, Luhmer M, Evano G, Fishing with copper acetylides: Selective
alkynylation of heteronucleophiles, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.09.053.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Fishing with Copper Acetylides: Selective
Alkynylation of Heteronucleophiles
Leave this area blank for abstract info.
Céline Guissarta, Michel Luhmerb, and Gwilherm Evanoa,
a Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Université libre de Bruxelles (ULB), Avenue F. D. Roosevelt 50,
CP160/06, 1050 Brussels, Belgium
b Laboratoire de Résonance Magnétique Nucléaire Haute Résolution, Service de Chimie et PhysicoChimie Organiques, Université libre de Bruxelles
(ULB), Avenue F. D. Roosevelt 50, CP160/08, 1050 Brussels, Belgium

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Fishing with Copper Acetylides: Selective Alkynylation of Heteronucleophiles
Céline Guissarta, Michel Luhmerb, and Gwilherm Evanoa,
a Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Université libre de Bruxelles (ULB), Avenue F. D. Roosevelt 50,
CP160/06, 1050 Brussels, Belgium
b Laboratoire de Résonance Magnétique Nucléaire Haute Résolution, Service de Chimie et PhysicoChimie Organiques, Université libre de Bruxelles (ULB),
Avenue F. D. Roosevelt 50, CP160/08, 1050 Brussels, Belgium
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Copper acetylides are readily available and especially convenient reagents for the
alkynylation of a broad range of heteronucleophiles. Upon simple activation with molecular
oxygen in the presence of suitable ligands and solvents, they readily transfer their alkyne
moiety at room temperature, notably yielding a variety of nitrogen- and phosphorus-
substituted alkynes. We report in this manuscript an extensive study of the chemoselectivity
of this alkynylation based on quantitative 13C NMR analyses. With suitable ligand/solvent
combinations, various phosphorus-based nucleophiles can be alkynylated with excellent
levels of selectivity, even in the presence of a large excess of nitrogen-nucleophiles. This
chemoselective alkynylation could be further extended to an even more challenging selective
alkynylation of a nitrogen-nucleophile over another one, further highlighting the synthetic
potential of copper acetylides as alkynylating agents that can selectively “fish” a nucleophile
without affecting others.
Available online
Dedicated to Prof. Léon Ghosez on the occasion of
his retirement from Editorship of Tetrahedron and
for his remarkable contributions to organic synthesis
Keywords:
Alkynylation
Copper Acetylides
Chemoselectivity
Ynamides
Alkynylphosphonates
Ynimines
Quantitative 13C NMR
2018 Elsevier Ltd. All rights reserved.
1. Introduction
attractiveness, this approach has however been widely
investigated and has resulted in the design of highly efficient,
robust and selective reactions, the copper-catalyzed alkyne-azide
cycloaddition4 and related “click” processes5 certainly being the
most representative examples to date.
Among all criteria that have to be taken into account for the
development of new transformations, chemoselectivity is
certainly one of the most crucial. Processes featuring exquisite
levels of chemoselectivity are indeed of utmost importance, for
various reasons. Firstly, they avoid tedious, lengthy and wasteful
protection/deprotection steps required to mask the reactivity of
functional groups that would not be tolerated by non-
chemoselective transformations, therefore resulting in step-
economical syntheses.1 Secondly, they enable easy site-selective
functionalizations of polyfunctional molecules, therefore
facilitating late-stage functionalization and diversity-oriented
syntheses.2 Moreover, such reactions can be used for the selective
Among these chemoselective reactions, the ones enabling
orthogonal and switchable selectivities are even more attractive
both in terms of efficiency and versatility. Not surprisingly, such
processes are still rare6 and the most significant examples include
Buchwald’s remarkable selective copper-catalyzed N- and O-
arylation of aminoalcohols,7 Alper’s chemodivergent palladium-
catalyzed carbonylation of aminophenols,8 Mashima’s
chemoselective acylation of aminoalcohols9 or Miller’s selective
acylations of erythromycin A.10
labelling,
chemical
modification,
functionalization
or
bioconjugation of complex biomolecules, which has notably had
a deep impact in chemical biology and biomedical research.3 Last
but not least, they can be utilized as “chemical warheads” for the
functionalization of a given molecule in the presence of others.
In this context, and based on our long-standing interest in the
alkynylation of heteronucleophiles,11-14 we became interested in
assessing the chemoselectivity of such processes with the
objective to develop either chemodivergent procedures or to be
able to selectively functionalize a given heteronucleophile in the
presence of a large excess of others. Among all the alkynylation
procedures and alkynylating agents we studied over the years,
copper acetylides 1,14 readily available and bench-stable reagents,
have proven to be the most versatile ones. While these polymeric
solids are totally inert under most conditions, we have shown that
they can be readily activated by molecular oxygen in the
presence of suitable ligands, enabling remarkably efficient
While there are many biological systems that are tailored
towards specific substrates and that operate with ultimate levels
of chemoselectivity, synthetic ones are much more challenging
since they rely on much more basic approaches and parameters to
ensure decent levels of selectivity. It does therefore represent a
highly demanding challenge to develop reagents, catalysts and
conditions that can reliably target, with surgical precision, a
single reactive functional group out of many. Due to its

2
Tetrahedron
alkynylation of a range of nitrogen-based (lactams 2N,14a
Based on these specifications, “classical” techniques such as
ACCEPTED MANUSCRIPT
oxazolidinones 2N’,14a imines 2N”14b), phosphorus-based
HPLC, UPLC, SFC or GC were eliminated due to the need for a
lengthy optimization of the parameters for each nucleophile that
would be utilized for the study of the selectivity of the
(phosphine oxides 2P,14d phosphine-boranes 2P’,14c phosphites
2P”14a) and carbon-based (arenes 2C-C”
2C”’14f) nucleophiles 2 (Figure 1).
,
trifluoromethyl anion
14e
1
alkynylation. Moreover, H NMR analysis turned out to be of
little use in this case due to overlapping signals. We therefore
decided to focus our efforts on quantitative 13C NMR analysis, an
analytical method that is clearly under-utilized by synthetic
chemists despite its strong potential and reliability.
2.1. Assessing the feasibility and reliability of quantitative 13
NMR analyses for the study of the alkynylation of
heteronucleophiles with copper acetylides.
C
Quantitative analysis of product ratios is indeed more
conveniently performed with 13C NMR spectroscopy15,16 due to
the greater range of chemical shift compared to 1H NMR
spectroscopy. In addition, natural-abundance 13C NMR can be
employed with rather limited amounts of material (in the tens of
mg range) and yields spectra that exhibit simple first-order
patterns, typically singlet signals in 1H-decoupled spectra.
However, this technique generally requires long measurement
times for the analyses to be quantitative and to achieve sufficient
signal-to-noise ratio. More precisely, a long relaxation delay (D1)
is required for the longitudinal magnetizations, i.e. the nuclear
spin-state populations, to return to equilibrium before the next
pulse. Typically, this recovery process exhibits an exponential
time-dependence and is characterized by a single relaxation time
T1. For spectra recorded using a flip angle of 90°, the repetition
time, which is defined as the sum of the acquisition time (AQ)
and D1, must be at least five times the longest T1 value (Figure
2). Furthermore, quantitative 13C NMR spectra must be recorded
with inverse-gated broadband 1H decoupling, i.e. with 1H
irradiation turned on only during acquisition (Figure 2), to
prevent the buildup of nuclear Overhauser effects. This results in
a significant drop in signal-to-noise ratio compared to routine
spectra and this has to be compensated by further signal
averaging. Considering that T1 values can reach several tens of
seconds for 13C, it is clear that longitudinal relaxation is a central
issue in quantitative analysis.
Figure 1. Oxidative alkynylation of N-, P-, and C- nucleophiles
with copper acetylides.
Based on the strong solvent and ligand effects on these
procedures, we envisioned that the chemoselective alkynylation
of a given nucleophile in the presence of another one might be
possible with the proper choice of both the ligand and solvent
(Scheme 1): we report in this manuscript our efforts towards this
chemoselective oxidative alkynylation.
θ
13C
D1: relaxation delay
P1: pulse width
θ: flip angle
Scheme 1. Goal of this study: chemoselective alkynylation with
copper acetylides.
AQ: acquisition time
D1
P1
AQ
2. Results and discussion
Decoupling
1H
Figure 2. Pulse sequence for the acquisition of 13C NMR spectra
With this goal in mind, we first needed to select the most
convenient analytical method that would allow for a fast and
reliable quantification of the selectivity of the oxidative
alkynylation of a mixture of two heteronucleophiles with a
copper acetylide. For this method to be of any usefulness, it
should meet the following criteria: (i) it should be non-
destructive in order to be able to recover, if required, the
alkynylated product(s) after quantitative analysis, (ii) it should
allow for a reliable and reproducible quantitative analysis with a
small margin of error, (iii) it should be applicable to the analysis
of the alkynylation of a broad range of heteronucleophiles with
no or minimum re-optimization of the analysis parameters and
settings and, (iv) it should be easily amenable to a fast screening
of ligands and solvents for the alkynylation.
with inverse-gated 1H decoupling.
One possibility to shorten the T1 relaxation times, and
therefore be able to perform a quantitative 13C NMR analysis in a
reasonable measurement time, is to use a paramagnetic relaxation
agent.
Dipolar interactions with unpaired electrons, whose
1
magnetic moment is about 658 times larger than that of H, will
then dominate and substantially speed up the 13C relaxation
processes.
If we now consider the system we want to study (Scheme 1),
the first step is therefore to choose a relaxation agent that would
allow for a sufficient decrease of T1 relaxation times but would
not cause significant line broadening. Importantly, the relaxation
agent should not interfere, complex or react with any species

3
present in the reaction mixture. Considering the fact that
paramagnetic copper(II) salts are generated in a quantitative
manner after the oxidative alkynylation, we first envisioned using
these byproducts as inherent relaxation agents. After considerable
experimentation, we could not however obtain reliable enough
quantitative 13C NMR analyses and therefore switched to the
commonly used relaxation agent chromium(III) acetylacetonate,
Cr(acac)3.
Having demonstrated the efficiency of Cr(acac)3 as
ACCEPTED MANUSCRIPT
relaxation agent and optimized the acquisition parameters, we
next decided to ascertain the viability of our procedure for the
quantitative analysis of a mixture of two representative hetero-
substituted alkynes, a crucial point before its use with real
systems. With this goal in mind, we therefore prepared a series of
mixtures containing known quantities of alkynylphosphonate
3P”a and ynamide 3N’a together with nitrocyclohexane IS, a
compound which is totally inert towards the different species
involved in our whole study and which was therefore selected as
an internal standard. The signal of the carbon bearing the nitro
substituent has in addition a chemical shift that is in the center of
the spectral window and will not overlap with those of the
compounds we want to study. Precisely measured quantities of
the three compounds were therefore dissolved in CDCl3 together
with Cr(acac)3 (to reach the 0.075 M optimal concentration):
gratifyingly, the analysis of these samples with the optimized
conditions summarized in Figure 3 demonstrated that the ratio
determined by 13C NMR are in excellent agreement with the
calculated ones (≤5%). A representative 13C NMR spectrum of
such a model mixture is shown in Figure 3.
The optimum concentration of this agent was first determined
using the model alkynylation of diethylphosphite 2P”a with oct-1-
ynylcopper 1a, a reaction we had previously shown to smoothly
provide alkynylphosphonate 3P”a (Scheme 2). After reaction with
2
equivalents of N-methyl-imidazole in DMF under an
atmosphere of oxygen for 16 hours at 25 °C (to make sure the
analyses would not be biased by variations of the room
temperature), the crude reaction mixture was quenched with an
aqueous mixture of saturated ammonium chloride and 28%
ammonium hydroxide (1:1 solution) to remove all copper salts,
and extracted with ethyl acetate. Combined organic layers were
next washed with water and brine, dried over MgSO4, filtered
and concentrated to dryness. The crude mixture was finally
dissolved in CDCl3 (1 mL) before adding the relaxation agent,
Cr(acac)3. By measuring the 13C T1 relaxation times by means of
the inversion-recovery method, we determined that the use of
0.075 M of Cr(acac)3 is ideal and allows for relaxation times
below 0.6 s for all carbons of alkynylphosphonate 3P”a, without
significant signal broadening. We also checked its stability in the
presence of the relaxation agent and no degradation could be
observed, even after 10 days. We then adjusted the acquisition
parameters and recorded a 13C spectrum (Figure 3) from which
we extracted integral data for all the signals of 3P”a. These data
confirmed the quantitative analysis and, which is an important
point for our studies, demonstrated that we could compare the
intensities measured for carbon bearing a different number of
hydrogen atoms, including quaternary carbons. As a note,
deconvolution was not strictly required to obtain reliable results.
2.2. Chemoselective alkynylation of phosphites vs
oxazolidinones.
Having demonstrated the feasibility and the reliability of
quantitative 13C NMR analyses that enable an excellent
discrimination between an ynamide and an alkynylphosphonate
and the quantification of the ratio of these two heterosubtituted
alkynes, we next moved to a systematic screening of the
influence of the nature of both the ligand and solvent on the
chemoselectivity. Oct-1-ynylcopper 1a was selected as a model
copper acetylide for this study and was reacted with 2 equivalents
of diethylphosphite 2P”a and oxazolidinone 2N’a – both
nucleophiles being excellent reaction partners for oxidative
alkynylations with copper acetylides, reactions that in addition
proceed at similar rates14a – in the presence of representative
ligands (1 equivalent in the case of bidentate ligands, 2 in the
case of monodentate ones) and solvents that we previously found
to be efficient for the oxidative alkynylation of various
heteronucleophiles under an atmosphere of oxygen (balloon) at
Scheme 2. Model reaction selected for the validation of the
quantitative 13C NMR analysis.
90°
13C
7.9 µs
3 s
0.5 s
Decoupling
1H
3P”a/IS
3N’a/IS
3P”a/3N’a
Sample
Calc. NMR Diff. Calc. NMR Diff. Calc. NMR Diff.
1
3
4
0.865 0.887 3% 0.843 0.834 1% 1.026 1.063 4%
0.930 0.979 5% 0.220 0.223 1% 4.216 4.390 4%
0.151 0.157 4% 0.140 0.142 1% 1.076 1.100 2%
Figure 3. Optimized 13C NMR pulse sequence, analysis of product ratios in model mixtures and representative 13C NMR spectrum (100
MHz, CDCl3, 25 °C). The α and β notation refers to the two resonances observed for the C1 carbon coupling with a phosphorous nucleus.

4
Tetrahedron
25 °C for 16 h and with a stirring rate of 375 rpm. The crude
previously showed to promote a fast and high-yielding
ACCEPTED MANUSCRIPT
mixtures were then treated as previously described and dissolved
in CDCl3 (1 mL) before adding 1 equivalent of the internal
standard, nitrocyclohexane, and Cr(acac)3 (0.075 M).
Quantitative 13C NMR analyses of the crude mixtures according
to our optimized procedure described above enabled the
determination of the yields of alkynylphosphonate 3P”a and
ynamide 3N’a: results from these studies are collected in Figure 4.
alkynylation of 2N’a regardless the nature of the solvent,14a also
highlights the dramatic influence of the phosphite on its
alkynylation.
Having determined the optimal system for the selective
alkynylation of a phosphite in the presence of an oxazolidinone,
we next decided to further push its limits by increasing the
amount of oxazolidinone. Another set of experiments was
therefore performed using 2, 4, 6, 10 and 20 equivalents of
oxazolidinone 2N’a compared to the starting phosphite 2P”a. The
exact same procedure was utilized to obtain the quantitative 13C
NMR yields and product ratios. As evidence by the results
summarized in Figure 5, the chemoselectivity was in favor of the
alkynylation of the phosphite in all cases, even in the presence of
20 equivalents of oxazolidinone, a quite remarkable feature.
Quite logically, the amount of ynamide 3N’a increased together
with the proportion of oxazolidinone, reaching however only 7%
with 20 equivalents.
Figure 4. Ligand and solvent effects on the chemoselectivity of
the oxidative alkynylation of a phosphite vs an oxazolidinone
with a copper acetylide. Quantitative 13C NMR yields determined
with nitrocyclohexane as internal standard and Cr(acac)3 as
relaxation agent.
As evidenced by these results, there is a net selectivity in
favor of the alkynylation of the starting phosphite 2P”a, the
corresponding alkynylphosphonate 3P”a being formed
predominantly or exclusively. Importantly, the reactions went to
completion in all cases, the difference to 100% of the added
products yields corresponding to competing dimerization and
protonation of the starting copper acetylide.
Figure 5. Influence of the amount of oxazolidinone on the
chemoselectivity of the oxidative alkynylation of a phosphite.
Quantitative 13C NMR yields determined with nitrocyclohexane
as internal standard and Cr(acac)3 as relaxation agent.
To further assess the efficiency of our conditions, we next
evaluated the generality of this chemoselective alkynylation by
reacting various copper acetylides 1 with 2 equivalents of
diethylphosphite 2P”a and 20 of oxazolidinone 2N’a under our
optimized conditions. The chemoselectivity was assessed by
quantitative 13C NMR analyses of crude reaction mixtures and by
comparison with 13C NMR data of all possible pure alkynylated
products prepared according to our previously reported
procedures.14 As highlighted by results collected in Figure 6, a
total chemoselectivity was observed, for some unclear reason,
with all aromatic copper acetylides. The resulting
alkynylphosphonates 3P”b-f are in addition formed in higher
yields compared to 3P”a, regardless of the electronic nature of the
aryl group. All together, these results further highlight the
robustness of our procedure that enables selectively “fishing” a
phosphite in the presence of a large excess of an oxazolidinone.
To conclude this study, the influence of the starting phosphite 2P”
was finally evaluated in combination with oct-1-ynylcopper 1a:
its nature was shown to have a limited impact on the
chemoselectivity, the corresponding alkynylphosphonates
Among the five ligands evaluated, phenanthroline turned out
to be by far the most efficient one, promoting the formation of
3P”a with a complete chemoselectivity regardless of the nature of
the solvent. The best solvent used in combination with this ligand
was found to be acetonitrile, favoring the alkynylation to 3P”a in
64% yield. Compared to our originally reported procedure for the
oxidative alkynylation of phosphites,14a which relied on the use of
N-methyl-imidazole as the ligand in DMF, the presence of the
additional oxazolidinone clearly has a deep impact on the
alkynylation since, in the absence of this extra nucleophile,
N-methyl-imidazole was found to be a better ligand for the
alkynylation of phosphites compared to phenanthroline, therefore
revealing a subtle effect of the competing coordination of the
ligand and the nucleophiles to the oxidized copper acetylide. The
use of bidentate ligand certainly inhibits the coordination of the
oxazolidinone, a weaker ligand for copper than the phosphite,
which might account for both the ligand effect observed and the
chemoselectivity of the alkynylation. The absence of even traces
of ynamide 3N’a with TMEDA as the ligand, which we

5
3 a,g,h being predominantly formed together with minor
amounts of the corresponding ynamide 3N’a (5-7%). In the case
of diisopropylphosphite, the reduced efficiency of its oxidative
alkynylation can be attributed to increased steric hindrance close
to the reacting center and its reduced ability to coordinate copper.
To further assess and expand the scope of this
ACCEPTED MANUSCRIPT
P”
chemoselective alkynylation, we then moved to other N- and P-
nucleophiles: this study is described in the following section.
2.3. Chemoselective alkynylation of P- and N- nucleophiles.
To further investigate the influence of the nature of both the P-
and N- nucleophiles on their alkynylation, we indeed briefly
investigated the behavior of other nucleophiles for which we had
previously shown that they could be successfully transformed to
the corresponding phosphorus- or nitrogen- substituted alkynes.14
With this goal in mind, diphenylphosphine oxide 2Pa and
dicyclohexylphosphine-borane 2P’a were first reacted with oct-1-
ynylcopper 1a in the presence of 10 equivalents of oxazolidinone
2N’a under the conditions optimized for the selective alkynylation
of phosphites (Figure 7). To our greatest pleasure, the same trend
was observed with these two P-nucleophiles since the
corresponding
phosphorus-substituted
alkynes,
namely
alkynylphosphine oxide 3Pa and alkynylphosphine-borane 3P’a
were formed as the exclusive or major products, respectively, the
lower yield obtained for 3P’a being attributed to its lower stability
under the reaction conditions.
We could moreover also successfully demonstrate that the
chemoselective alkynylation of phosphites in the presence of N-
nucleophiles is not limited to oxazolidinones since
alkynylphosphonate 3P”a was still found to be the major product
in the presence of an excess of γ-lactam 2Na, its alkynylation to
3Na being limited, especially when considering the 10/1 ratio
between 2P”a and 2Na utilized.
Having previously demonstrated that imines readily react with
copper acetylides under oxidative conditions,14b we finally moved
to the study of the selectivity of the alkynylation of
diethylphosphite 2P”a in the presence of benzophenone imine
2N”a. In this case, the use of an excess of this nucleophile was
prohibited since it could not be eliminated during the workup,
which considerably complicated further quantitative 13C NMR
analyses. A 1:1 ratio of 2P”a and 2N”a was therefore utilized and a
high selectivity in favor of the phosphite was observed again in
this case. This selectivity was in addition shown to be
independent of the nature of the starting copper acetylide 1 as
demonstrated
with
the
exclusive
formation
of
alkynylphosphonates 3P”a-f, not a trace of the ynimines 3N”a-f
being detected in crude reaction mixtures.
Remarkably, a screening of ligands (not shown) revealed that
the chemoselectivity could be reversed, replacing 1,10-
phenanthroline by pyridine under the exact same conditions
favoring the formation of ynimine 3N”a, although formed in a
modest 33% yield due to competing dimerization and protonation
of the starting copper acetylide 1a, over the alkynylation of
diethylphosphite 2P”a to 3P”a (6%).
Figure 6. Assessing the generality of the chemoselective
oxidative alkynylation of phosphites in the presence of an
oxazolidinone. Quantitative 13C NMR yields determined with
nitrocyclohexane as internal standard and Cr(acac)3 as
relaxation agent. * denotes isolated yields.
As evidenced by all results described in this section, copper
acetylides can be utilized as highly selective alkynylation agents
provided that the right ligand/solvent combination is utilized. In a
final attempt to bring this chemoselective alkynylation one step
further, we finally addressed a more complicated case in which
two nitrogen-nucleophile could compete with the activated
copper acetylides, which is at the core of the next and final
section of this article.
At this point of our studies, we have demonstrated the
feasibility of
a chemoselective oxidative alkynylation of
phosphites, even in the presence of a 10-fold excess of an
oxazolidinone. The nature of the starting copper acetylide was
shown to have a pronounced effect on the chemoselectivity, aryl-
substituted ones providing full control of the chemoselectivity
while the use of an alkyl-substituted one still provides minor
amounts of an ynamide in the presence of a large excess of the
oxazolidinone compared to the starting phosphite.

6
Tetrahedron
ACCEPTED MANUSCRIPT
Figure 7. Chemoselective alkynylation of P- and N- nucleophiles. Quantitative 13C NMR yields determined with nitrocyclohexane as
internal standard and Cr(acac)3 as relaxation agent.
O
O
2.4. Chemoselectivity of the oxidative alkynylation of two N-
nucleophiles.
O2
O
O
H
N
C6H13
N
(1 equiv.
if bidentate,
2 equiv.
2N'
a
3N'a
For this study, we selected two nucleophiles with different
coordination properties towards copper in order to maximize the
chances of success of this challenging reaction: oxazolidinone
2N’a and benzophenone imine 2N”a. The exact same systematic
study of the influence of both the ligand and solvent performed
for the competition experiments between an oxazolidinone and a
phosphite was then undertaken in order to assess the
chemoselectivity of the alkynylation: results from this study are
illustrated in Figure 8. Due to the close reactivity between the
two heteronucleophiles evaluated, ynamide 3N’a and ynimine
3N”a are readily formed with a number of ligand/solvent
combinations, ynamide 3N’a being the major product in most
cases. Although benzophenone imine 2N”a could not be
alkynylated in a fully selective manner, various systems
promoted a clean and totally chemoselective alkynylation of
oxazolidinone 2N’a to the corresponding ynamide 3N’a, the best
compromise between efficiency and selectivity being obtained
using TMEDA in dichloromethane which afforded 3N’a in 75%
yield together with only 5% of 3N”a.
(2 equiv.)
if monodentate)
C6H13
Cu
+
and
+
(0.5 M)
25 °C, 16h
H
N
C6H13
N
1a
Ph
Ph
Ph
2N"
Ph
a
3N"
a
(2 equiv.)
The chemoselectivity of this oxidative alkynylation was
finally tested starting from another oxazolidinone, 2N’b: upon
reaction with oct-1-ynylcopper 1a and TMEDA in
Figure 8. Ligand and solvent effects on the chemoselectivity of
the oxidative alkynylation of an oxazolidinone vs an imine with a
copper acetylide. Quantitative 13C NMR yields determined with
nitrocyclohexane as internal standard and Cr(acac)3 as
relaxation agent.
dichloromethane in the presence of
2
equivalents of
benzophenone imine 2N”a , ynamide 3N’g could be selectively
formed in 74% yield without a trace of ynimine 3N”a (Scheme 3),
therefore confirming the generality of this chemoselective
alkynylation.

7
coordination of the nucleophile(s) to copper and the effect of
ACCEPTED MANUSCRIPT
the ligand on the ease of the oxidation and disproportionation
steps as well as on the stability of copper acetylide intermediates
also have a clear influence on both the outcome and the
selectivity of the reaction.
3. Conclusions and outlook
In continuation of our studies on the use of copper acetylides
as readily available and convenient reagents for the alkynylation
of heteronucleophiles, we have now demonstrated, based on
quantitative 13C NMR analyses, that they can in addition be used
for chemoselective alkynylations. With suitable ligand/solvent
Scheme 3. Chemoselective oxidative alkynylation of
5-(chloromethyl)oxazolidin-2-one
in
the
presence
of
benzophenone imine. Quantitative 13C NMR yield determined
with nitrocyclohexane as internal standard and Cr(acac)3 as
relaxation agent.
combinations,
various
phosphorus-based
nucleophiles
(phosphites, phosphine oxides, phosphine boranes) can be
alkynylated with excellent levels of selectivity, even in the
presence of
a
10-fold excess of nitrogen-nucleophiles
2.5. Discussion of the chemoselectivity of the oxidative
alkynylation of two N-nucleophiles.
(oxazolidinones, lactams, imines). This chemoselective
alkynylation could be further extended to the quite challenging
selective alkynylation of a nitrogen-nucleophile, namely an
oxazolidinone, over another one, further highlighting the
synthetic potential of copper acetylides. “Fishing” with copper
acetylides clearly has a strong potential for the selective
modification of a heteronucleophile in a complex mixture, which
should be quite handy for the site-selective functionalization of
polyfunctional molecules, late-stage functionalizations, selective
labelling or bioconjugation of complex biomolecules. Further
studies on the reactivity of copper acetylides, on the mechanism
associated to their oxidative activation and on their use for the
modification of complex and polyfunctional molecules are
underway and will be reported in due course.
In order to be able to discuss the trends observed for the
chemoselective alkynylation with copper acetylides, we first need
to discuss its mechanism. The first step of the reaction involves
simultaneous oxidation of the starting copper(I) acetylide 1 by
molecular oxygen and the coordination of both the ligand L (2
ligands in the case of a monodentate one, 1 in the case of
bidentate ligands) and the heteronucleophile 2 yielding to a
putative copper(II) acetylide species 4 (Scheme 4). Indeed, we
have demonstrated that 1 is totally inert towards all ligands and
heteronucleophiles discussed in this study and that it does not
either readily react when treated with molecular oxygen in the
presence of a ligand or a heteronucleophile only: molecular
oxygen, a nucleophile and a ligand are therefore required to
trigger the reaction. Dismutation of this copper(II) acetylide 4 to
the corresponding copper(I) 5 and copper(III) 6 acetylides, as in
the Cham-Lam-Evans reaction,17 would then occur, the former
being re-oxidized by molecular oxygen to 4 while the later would
undergo a final reductive elimination yielding heterosubstituted
alkyne 3 and a copper(I) complex 7 that would eventually be
oxidized to the corresponding copper(II) complex 8.
4. Experimental section
4.1. General methods and materials
All reactions were carried out in oven-dried glassware under
an oxygen atmosphere. Dichloromethane and acetonitrile were
freshly distilled from calcium hydride under argon.
N,N-dimethylformamide and dioxane were bought over
molecular sieves in AcroSeal® bottles from Acros Organics and
used as supplied. Copper acetylides were prepared according to
our previously reported procedure.14a,f,h All other reagents were
used as supplied.
4.2. 13C NMR parameters and processing
13C spectra were recorded at 25°C using an internal deuterium
lock on a Varian VNMRS 400 spectrometer, operating at 100.56
MHz for 13C, equipped with a 5 mm Automated Triple
Broadband (ATB) probe. The solvent was used as internal
standard for chemical shift referencing (δC 77.16 ppm for
CDCl3). The spectra were recorded in 3 h with the following
acquisition parameters: a spectral width of 254 ppm (25510 Hz)
centered at about 90 ppm, a 90° pulse width of 7.9 µs, an
acquisition time of 0.5 s, a relaxation delay D1 of 3 s and 3600
Scheme 4. Proposed mechanism for the oxidative alkynylation of
heteronucleophiles with copper acetylides.
1
repetitions. H decoupling was applied only during acquisition
(inverse-gated decoupling) using a WALTZ-16 scheme with a 1H
pulse width of 85 µs. The processing, which was completed with
the software VNMRJ, included exponential apodization of the
FID with a line-broadening factor (lb) of 2 Hz, zero-filling up to
256k points, Fourier transform, phase correction, chemical shift
referencing and baseline correction. The integration limits were
fixed at ± 0.3 ppm with respect to the center of each peak unless
another peak was present in this range. In that case, a common
boundary was set right in between these two peaks.
Based on this mechanism, the discrimination between two
heteronucleophiles happens during the very first step of the
process yielding to copper(II) acetylide 4 coordinated to both the
ligand and the deprotonated nucleophile. As a simplification,
nucleophiles with better coordinating properties to copper(II)
would be therefore preferentially alkynylated, which is in
agreement with the fact that phosphites, which are better ligands
for copper(II) than oxazolidinones, selectively react with copper
acetylides. The strong ligand and solvent effects observed and the
reversal of selectivity observed with phosphites and imines
however show that the situation is not that simple: multiple

8
Tetrahedron
4.3. General procedure for the oxidative alkynylations, sample
1417, 1217, 1199, 1164, 1031, 818, 746, 707 cm-1; ESIHRMS
ACCEPTED MANUSCRIPT
preparation for quantitative 13C NMR analysis and
characterization data
m/z calcd for C12H12NO2 [M+H]+ 202.0868, found 202.0870.
4.3.1.7. Diethyl ([1,1'-biphenyl]-4-ylethynyl)
A 5 mL round bottom flask was successively charged with the
two nucleophiles (1.0 mmol to 10.0 mmol), the alkynylcopper
reagent (0.5 mmol) and the solvent (1 mL). The resulting bright
yellow slurry was then treated with the ligand (0.5 mmol if
bidentate and 1.0 mmol if monodentate) and the reaction mixture
was stirred at 25 °C for 16 hours and at 375 rpm and under an
atmosphere of oxygen (balloon). The reaction was then diluted
with 15 mL of an aqueous mixture of saturated ammonium
chloride and 25% ammonium hydroxide (1:1 solution) and
extracted with 3x10 mL of ethyl acetate. Combined organic
layers were washed with 10 mL of water and 10 mL of brine,
dried over MgSO4 and concentrated to dryness. Nitrocyclohexane
(65 µL, 0.5 mmol) and chromium(III) acetylacetonate (27 mg, 75
µmol) were added to the crude and it was dissolved in 1 mL of
CDCl3.
phosphonate 3P ” d. This compound has been previously
reported.1 9 White solid; 1H NMR (400 MHz, CDCl3): δ 7.62-7.52
(m, 6H), 7.45-7.39 (m, 2H), 7.37-7.32 (m, 1H), 4.27-4.17 (m,
4H), 1.39 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ
143.4, 139.6, 133.0 (d, JC-P = 2.4 Hz), 128.9, 128.2, 127.1, 127.0,
118.2 (d, JC-P = 5.5 Hz), 99.0 (d, JC-P = 53.1 Hz), 78.9 (d, JC-P
299.5 Hz), 63.2 (d, JC-P = 5.6 Hz), 16.1 (d, JC-P = 7.1 Hz).
=
4.3.1.8. 3-([1,1'-biphenyl]-4-
ylethynyl)oxazolidin-2-one 3N ’ d. This compound has
1
been previously reported.21 White solid; H NMR (400 MHz,
CDCl3): δ 7.61-7.49 (m, 6H), 7.47-7.41 (m, 2H), 7.38-7.32 (m,
1H), 4.53-4.47 (m, 2H), 4.06-4.00 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 156.0, 141.1, 140.4, 132.1, 129.0, 127.8, 127.1 (2C),
121.2, 79.7, 71.3, 63.2, 47.2.
4.3.1.9. Diethyl
(4-fluorophenylethynyl)
Some of these reactions were performed in duplicate to
compare the 13C NMR yields with the isolated ones.
phosphonate 3P ” e. This compound has been previously
reported.1 9 Colorless oil; H NMR (400 MHz, CDCl3): δ 7.50-
1
7.44 (m, 2H), 7.02-6.94 (m, 2H), 4.19-4.08 (m, 4H), 1.31 (dt, J =
7.1 Hz and JH-P = 0.7 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ
163.8 (d, JC-F = 253.5 Hz), 134.8 (dd, JC-F = 8.9 and JC-P = 2.4
Hz), 116.0 (d, JC-F = 22.3 Hz), 115.6 (dd, JC-P = 5.7 and JC-F = 3.5
Hz), 97.8 (d, JC-P = 53.1 Hz), 78.6 (d, JC-P = 243.1 Hz), 63.2 (d,
JC-P = 5.6 Hz), 16.1 (d, JC-P = 7.1 Hz).
4.3.1.1. Diethyl (oct-1-yn-1-yl)phosphonate 3P”1a.
This compound has been previously reported.18 Colorless oil; H
NMR (400 MHz, CDCl3): δ 4.07 (dt, J = 7.1 Hz and JH-P = 15.7
Hz, 4H), 2.27 (dt, J = 7.1 Hz and JH-P = 4.4 Hz, 2H), 1.57-1.45
(m, 2H), 1.39-1.16 (m, 6H), 1.29 (t, J = 7.1 Hz, 6H), 0.82 (t, J =
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 103.3 (d, JC-P = 53.2
Hz), 70.5 (d, JC-P = 303.3 Hz), 63.0 (d, JC-P = 5.5 Hz), 31.2, 28.6,
27.5, 22.6, 19.3 (d, JC-P = 4.6 Hz), 16.2 (d, JC-P = 7.2 Hz), 14.1.
4.3.1.10. 3-(4-Fluorophenylethynyl)oxazolidin-2-
1
one 3N ’ e. White solid; MP: 114°C; H NMR (300 MHz,
CDCl3): δ 7.45-7.38 (m, 2H), 7,04-6.95 (m, 2H), 4.48 (dd, J =
9.3 and 7.7 Hz, 2H), 4.00 (dd, J = 9.3 and 7.7 Hz, 2H); 13C NMR
(75 MHz, CDCl3): δ 162.6 (d, JC-F = 248 Hz), 156.0, 133.8 (d, JC-
4.3.1.2. 3-(Oct-1-yn-1-yl)oxazolidin-2-one
3N’a.
Pale yellow oil; 1H NMR (300 MHz, CDCl3): δ 4.39 (dd, J = 9.1
and 7.7 Hz, 2H), 3.86 (dd, J = 9.3 and 7.8 Hz, 2H), 2.28 (t, J =
7.0 Hz, 2H), 1.72-1.17 (m, 8H), 0.87 (t, J = 6.3 Hz, 3H); 13C
NMR (75 MHz, CDCl3): δ 156.8, 71.3 70.1, 62.9, 47.1, 31.4,
28.8, 28.6, 22.6, 18.5, 14.1; IR (ATR) ν max 2929, 2858, 2269,
1767, 1415, 1301, 1206, 1115, 1035, 976, 751 cm-1; ESIHRMS
m/z calcd for C11H18NO2 [M+H]+ 196.1338, found 196.1341.
= 8.4 Hz), 118.3 (d, JC-F = 3.5 Hz), 115.7 (d, JC-F = 21.9 Hz),
F
78.7, 70.3, 63.2, 47.1; IR (ATR) ν max 2268, 1754, 1416, 1208,
1195, 1165, 1091, 835, 744 cm-1; ESIHRMS m/z calcd for
C11H9FNO2 [M+H]+ 206.0617, found 206.0618.
4.3.1.11. Diethyl
(4-methoxyphenylethynyl)
phosphonate 3P ” f. This compound has been previously
reported.1 9 Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.46 (d,
J = 8.9 Hz, 2H), 6.83 (d, J = 8.9 Hz, 2H), 4.22-4.12 (m, 4H), 3.79
(s, 3H), 1.36 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ
161.5, 134.4, 114.3, 111.3 (d, JC-P = 5.7 Hz), 99.9 (d, JC-P = 53.8
Hz), 77.2 (d, JC-P = 302.1 Hz), 63.2 (d, JC-P = 5.5 Hz), 55.4, 16.1
(d, JC-P = 7.1 Hz).
4.3.1.3. Diethyl
(phenylethynyl)phosphonate
3P”b. This compound has been previously reported.19 Colorless
oil; 1H NMR (400 MHz, CDCl3): δ 7.51-7.47 (m, 2H), 7.38 (tt, J
= 7.5 and 1.4 Hz, 1H), 7.33-7.27 (m, 2H), 4.21-4.11 (m, 4H),
1.34 (dt, J = 7.1 Hz and JH-P = 0.7 Hz, 6H); 13C NMR (100 MHz,
CDCl3): δ 132.5 (d, JC-P = 2.4 Hz), 130.7, 128.5, 119.4 (d, JC-P
6.0 Hz), 99.0 (d, JC-P = 52.4 Hz), 78.3 (d, JC-P = 299.2 Hz), 63.2
(d, JC-P = 5.5 Hz), 16.1 (d, JC-P = 7.1 Hz).
=
4.3.1.12. 3-(4-Methoxyphenylethynyl)oxazolidin-
2-one 3N ’ f. This compound has been previously reported.2 0
1
4.3.1.4. 3-(Phenylethynyl)oxazolidin-2-one 3N ’ b.
White solid; H NMR (400 MHz, CDCl3): δ 7.39-7.35 (m, 2H),
This compound has been previously reported.20 Colorless oil; H
1
6.83-6.79 (m, 2H), 4.46-4.41 (m, 4H), 3.98-3.92 (m, 2H), 3.78 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 159.8, 156.2, 133.5, 114.1,
114.0, 77.7, 70.9, 63.1, 55.3, 47.2.
NMR (400 MHz, CDCl3): δ 7.48-7.40 (m, 2H), 7.37-7.28 (m,
3H), 4.54-4.45 (m, 2H), 4.07-3.97 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 156.0, 131.7, 128.4, 128.3, 122.3, 79.1, 71.3, 63.2,
47.2.
4.3.1.13. Dibenzyl (oct-1-yn-1-yl)phosphonate 3P”g.
Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.30-7.20 (m, 10H),
4.99 (d, JH-P = 8.7 Hz, 4H), 2.20 (dt, J = 6.3 Hz and JH-P = 4.5 Hz,
2H), 1.43 (tt, J = 7.5 and 6.6 Hz, 2H), 1.30-1.13 (m, 6H), 0.81 (t,
J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 135.7, 128.5,
127.6, 127.0, 104.4 (d, JC-P = 53.3 Hz), 70.3 (d, JC-P = 292.5 Hz),
68.3 (d, JC-P = 5.3 Hz), 31.2, 28.5, 27.3, 22.4, 19.2, 14.0; IR
(ATR) ν max 2923, 2205, 1452, 1260, 990 cm-1; ESIHRMS m/z
calcd for C22H28O3P [M+H]+ 371.1776, found 371.1774.
4.3.1.5. Diethyl (p-tolylethynyl)phosphonate 3P ” c.
This compound has been previously reported.1 9 Colorless oil; 1H
NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.0 Hz, 2H), 7.12 (d, J =
8.0 Hz, 2H), 4.22-4.12 (m, 4H), 2.32 (s, 3H), 1.35 (dt, J = 7.1 Hz
and JH-P = 0.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 141.3,
132.5 (d, JC-P = 2.4 Hz), 129.3, 116.4 (d, JC-P = 6.0 Hz), 99.6 (d,
JC-P = 53.2 Hz), 77.7 (d, JC-P = 300.5 Hz), 63.1 (d, JC-P = 5.5 Hz),
21.7, 16.1 (d, JC-P = 7.1 Hz).
4.3.1.14. Diisopropyl
(oct-1-yn-1-yl)
phosphonate 3P”h. Colorless oil; 1H NMR (400 MHz,
CDCl3): δ 4.51-4.34 (m, 2H), 2.01 (dt, J = 6.6 Hz and JH-P = 4.8
Hz, 2H), 1.25 (tt, J = 7.8 and 7.2 Hz, 2H), 1.11-0.96 (m, 6H),
1.02 (d, J = 6.6 Hz, 12H), 0.56 (t, J = 6.3 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 102.5 (d, JC-P = 52.5 Hz), 71.5 (d, JC-P = 300.0
Hz), 71.0 (d, JC-P = 22.5 Hz), 30.7, 28.1, 27.0, 23.4 (d, JC-P = 4.5
4.3.1.6. 3-(p-Tolylethynyl)oxazolidin-2-one 3N ’ c.
White solid; MP: 123°C; 1H NMR (300 MHz, CDCl3): δ
7.33 (d, J = 8.1 Hz, 2H), 7,11 (d, J = 7.8 Hz, 2H), 4.47 (dd, J =
9.3 and 7.7 Hz, 2H), 3.99 (dd, J = 9.3 and 7.7 Hz, 2H), 2.34 (s,
3H); 13C NMR (75 MHz, CDCl3): δ 156.1, 138.5, 131.7, 129.2,
119.0, 78.4, 71.4, 63.1, 47.2, 21.6; IR (ATR) ν max 2263, 1752,

9
Hz), 23.2 (d, JC-P = 4.9 Hz), 22.1, 18.8, 13.5; IR (ATR) ν max
2979, 2213, 1377, 1257, 983 cm-1; ESIHRMS m/z calcd for
C14H28O3P [M+H]+ 275.1776, found 275.1778.
129.4, 128.9, 128.8, 128.4 (2C), 128.2, 128.1, 127.9, 127.6,
ACCEPTED MANUSCRIPT
127.0 (2C), 123.8, 94.4, 92.9; IR (ATR) ν max 3059, 1485, 1445,
1323, 909, 840, 763, 670 cm-1.
4.3.1.22. N-(diphenylmethylene)-2-(4-
4.3.1.15. (Oct-1-yn-1-yl)diphenylphospgine oxide
3Pa. This compound has been previously reported.22 Yellow oil;
1H NMR (300 MHz, CDCl3): δ 7.85-7.77 (m, 4H), 7.50-7.41 (m,
6H), 2.43 (td, J = 7.1 and JH-P = 3.5 Hz, 2H), 1.61 (app. quint., J
= 7.5 Hz, 2H), 1.45-1.34 (m, 2H), 1.34-1.22 (m, 4H), 0.86 (t, J =
fluorophenyl)ethynamine 3N ” e. Orange solid; MP:
1
80 °C; H NMR (300 MHz, CDCl3): δ 7.70 (d, J = 7.3 Hz, 2H),
7.48-7.42 (m, 6H), 7.33 (d, J = 7.6 Hz, 2H), 7.16-7.12 (m, 2H),
6.86 (t, J = 8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 177.2,
162.3 (d, JC-F = 248 Hz), 137.8, 136.4, 133.4, 131.7, 130.2, 129.5,
128.8, 128.4, 128.1, 120.7, 115.4, 93.0, 91.6; IR (ATR) ν max
2987, 2966, 2900, 2172, 1392, 1254, 1066 cm-1; ESIHRMS m/z
calcd for C21H15NF [M+H]+ 300.1189, found 300.1203.
6.8 Hz, 3H) ; 13C NMR (75 MHz, CDCl3): δ 133.5 (d, JC-P
=
121.0 Hz), 132.1 (d, JC-P = 2.8 Hz), 130.9 (d, JC-P = 11.1 Hz),
128.6 (d, JC-P = 13.3 Hz), 109.9 (d, JC-P = 30.3 Hz), 75.0 (d, JC-P
174.0 Hz), 31.2, 28.6, 27.6 (d, JC-P = 1.5 Hz), 22.5, 19.8 (d, JC-P
3.0 Hz), 14.1.
=
=
4.3.1.23. N-(diphenylmethylene)-2-(4-
methoxyphenyl)ethynamine 3N ” f. Yellow oil; 1H
NMR (300 MHz, CDCl3): δ 7.80 (d, J = 6.1 Hz, 2H), 7.60-7.42
(m, 8H), 7.28 (d, J = 3.2 Hz, 1H), 7.21 (d, J = 6.7 Hz, 1H), 6.82
(d, J = 7.0 Hz, 2H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
176.3, 159.5, 133.2, 131.4, 129.9, 129.4, 128.8, 128.3, 128.0,
113.9, 94.7, 91.3, 55.3; IR (ATR) ν max 2958, 2825, 2166, 1603,
1505, 1438, 1324, 1239, 1172, 1023, 821, 688 cm-1; ESIHRMS
m/z calcd for C22H18NO [M+H]+ 312,1388 found 312.1388.
4.3.1.16. Dicyclohexyl(oct-1-yn-1-yl)phosphine-
1
borane 3P’a. White solid; MP: 41 °C; H NMR (300 MHz,
CDCl3): δ 2.34 (td, J = 6.8 and JH-P = 3.3 Hz, 2H), 1.94–1.65 (m,
12H), 1.54–1.18 (m, 18H), 0.89 (t, J = 7.0 Hz, 3H), 0.85– -0.28
(br. m, 3H); 13C NMR (75 MHz, CDCl3): δ 110.3 (d, JC-P = 10.3
Hz), 68.6 (d, JC-P = 93.0 Hz), 32.3 (d, JC-P = 37.6 Hz), 31.3, 28.5,
28.0 (d, JC-P = 1.4 Hz), 26.9 (d, JC-P = 3.5 Hz), 26.8, 26.6 (d, JC-P
= 3.9 Hz), 26.5, 26.0 (d, JC-P = 1.0 Hz), 22.6, 20.0 (d, JC-P = 2.1
Hz), 14.1; IR (ATR) ν max 2928, 2852, 2376, 2345, 2194, 1445,
1055, 1000, 852, 754, 740, 616, 517, 465, 406 cm-1; ESIHRMS
m/z calcd for C20H38PBNa [M+Na]+ 343.2702, found 343.2695.
4.3.1.24. 5-(Chloromethyl)-3-(oct-1-yn-1-
yl)oxazolidin-2-one 3N ’ g. Colorless oil; H NMR (300
1
MHz, CDCl3): δ 4.84-4.76 (m, 1H), 3.93 (A of ABX syst, J = 9.0
and 9.0 Hz, 1H), 3.73-3.65 (m, 3H), 2.24 (t, J = 7.0 Hz, 2H), 1.47
(app quint., J = 7.4 Hz, 2H), 1.37-1.20 (m, 6H), 0.84 (t, J = 6.6
Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 155.5, 72.5, 71.4, 69.5,
49.6, 44.4, 31.3, 28.7, 28.5, 22.5, 18.3, 14.0; IR (ATR) ν max
2967, 2927, 2268, 1764, 1420, 1223, 1113, 1050, 742 cm-1;
ESIHRMS m/z calcd for C12H19ClNO2 [M+H]+ 244.1104, found
244.1109.
4.3.1.17. 1-(Oct-1-yn-1-yl)pyrrolidin-2-one
3N a.
1
Pale yellow oil; H NMR (300 MHz, CDCl3): δ 3.57 (t, J =
7.4 Hz, 2H), 2.33 (t, J = 8.1 Hz, 2H), 2.23 (t, J = 7.2 Hz, 2H),
2.02 (app. quint, J = 7.6 Hz, 2H), 1.44 (app. quint, J = 7.2 Hz,
2H), 1.36-1.12 (m, 6H), 0.80 (t, J = 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 176.0, 72.5, 71.3, 50.0, 31.3, 29.5, 28.8, 28.5,
22.4, 18.6, 18.5, 14.0; IR (ATR) ν max 2930, 2857, 2260, 1719,
1399, 1367, 1297, 1218, 1169, 1091, 813, 756 cm-1; ESIHRMS
m/z calcd for C12H20NO [M+H]+ 194.1545, found 194.1542.
Acknowledgments
4.3.1.18. N-(Diphenylmethylene)-oct-1-yn-1-
amine 3N ” a. Pale orange oil; 1H NMR (300 MHz,
CDCl3): δ 7.73 (d, J = 7.5 Hz, 2H), 7.48-7.44 (m, 6H), 7.40-7.35
(m, 2H), 2.43 (t, J = 6.8 Hz, 2H), 1.45-140 (m, 2H), 1.31-1.23
(m, 6H), 0.88 (t, J = 9.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ
177.2, 138.2, 136.5, 131.2, 129.6, 129.2, 128.6, 128.3, 128.0,
96.5, 83.7, 31.5, 29.1, 28.4, 22.6, 20.3, 14.2; IR (ATR) ν max
2919, 2848, 2246, 1661, 1444, 1313, 1274, 761, 692, 638 cm-1;
ESIHRMS m/z calcd for C21H24N [M+H]+ 290.1909, found
290.1902.
Our work was supported by the Université libre de Bruxelles
(ULB) and the FNRS (Incentive Grant for Scientific Research n°
F.4530.13). Mr. Félix Devaux is gratefully acknowledged for
technical assistance.
4.3.1.19. N-(diphenylmethylene)-2-
phenylethynamine 3N ” b. Orange solid; MP: 85 °C;
1H NMR (300 MHz, CDCl3): δ 7.71 (d, J = 7.4 Hz, 2H), 7.50-
7.49 (m, 2H), 7.44-7.42 (m, 4H), 7.33 (d, J = 7.6 Hz, 2H), 7.16-
7.18 (m, 5H); 13C NMR (75 MHz, CDCl3): δ 177.7, 137.9, 136.3,
131.6, 131.5, 130.1, 129.5, 129.0, 128.8, 128.3, 128.1, 127.8,
124.7, 94.2, 91.9; IR (ATR) ν max 2966, 2899, 2181, 1388, 1235,
1065, 550 cm-1; ESIHRMS m/z calcd for C21H16N [M+H]+
282.1283, found 282.1291.
4.3.1.20. N-(diphenylmethylene)-2-(4-
methylphenyl)ethynamine 3N ” c. Orange solid; MP:
1
83 °C; H NMR (300 MHz, CDCl3): δ 7.80 (d, J = 6.1 Hz, 2H),
7.60-7.42 (m, 8H), 7.28 (d, J = 3.2 Hz, 1H), 7.21 (d, J = 6.7 Hz,
1H), 6.82 (d, J = 7.0 Hz, 2H), 3.81 (s, 3H); 13C NMR (75 MHz,
CDCl3):
176.3, 159.5, 133.2, 131.4, 129.9, 129.4, 128.8,
128.3, 128.0, 113.9, 94.7, 91.3, 55.3; IR (ATR) ν max 3057, 1504,
1445, 1322, 808, 766, 693 cm-1.
4.3.1.21. N-(diphenylmethylene)-2-([1,1'-
biphenyl]-4-yl)ethynamine 3N ” d. Orange solid; MP:
1
90 °C; H NMR (300 MHz, CDCl3): δ 7.89-7.83 (m, 2H), 7.68-
7.51 (m, 9H), 7.50-7.29 (m, 8H) 13C NMR (75 MHz, CDCl3): δ
177.6, 140.6, 140.5, 138.3, 135.6, 132.1, 130.1, 129.7, 129.6,

10
Tetrahedron
References and notes
ACCEPTED MANUSCRIPT
Supplementary Material
23
Copies of 1H and 13C NMR spectra for all products, copies
of 13C NMR spectra and selected data for quantitative 13C
NMR analyses.
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