Convenient and practical alkynylation of heteronucleophiles with copper acetylides

Article abstract of DOI:10.1055/s-0033-1341025

Copper acetylides, readily available reagents which are characterized by their lack of reactivity, can be simply activated by oxidation with oxygen in the presence of simple nitrogen ligands such as TMEDA or imidazole derivatives. Upon activation, these nucleophilic species undergo a formal umpolung and can transfer their alkyne subunit to a wide range of heteronucleophiles, including amides, oxazolidinones, imines, and dialkyl phosphites. This alkynylation, which provides one of the most practical entry to useful building blocks such as ynamides, ynimines, and alkynylphosphonates, proceeds under especially mild conditions and can be easily performed on a multigram scale. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1341025

PRACTICAL SYNTHETIC PROCEDURES
▌A
pCraoctincavl seynnthieeticnptrocaednudres Practical Alkynylation of Heteronucleophiles with Copper
Acetylides
Alkynylation of Heteronucleophiles with Copper Acetylides
Cédric Theunissen,a Morgan Lecomte,a Kévin Jouvin,b Anouar Laouiti,b,c Céline Guissart,a Jérémy Heimburger,b
Estelle Loire,b Gwilherm Evano*a
a
Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Université Libre de Bruxelles,
Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
b
Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles Saint-Quentin en Yvelines, 45 Avenue des Etats-Unis,
78035 Versailles Cedex, France
c
Laboratoire de Chimie Hétérocyclique, Produits Naturels et Réactivité, Département de Chimie, Faculté des Sciences de Monastir,
Université de Monastir, Avenue de l’environnement, 5019 Monastir, Tunisia
Fax +32(2)6502798; E-mail: gevano@ulb.ac.be
PSP
Received: 17.02.2014; Accepted after revision: 25.02.2014
Dedicated to Prof. François Couty on the occasion of his 50th birthday
No271
Abstract: Copper acetylides, readily available reagents which are characterized by their lack of reactivity, can be simply activated by ox-
idation with oxygen in the presence of simple nitrogen ligands such as TMEDA or imidazole derivatives. Upon activation, these nucleo-
philic species undergo a formal umpolung and can transfer their alkyne subunit to a wide range of heteronucleophiles, including amides,
oxazolidinones, imines, and dialkyl phosphites. This alkynylation, which provides one of the most practical entry to useful building blocks
such as ynamides, ynimines, and alkynylphosphonates, proceeds under especially mild conditions and can be easily performed on a multi-
gram scale.
Key words: copper acetylides, alkynylation, ynamides, ynimines, alkynylphosphonates
O
X
HN
R3
O
R2
TMEDA =
3 (X = CH2, O)
X
R1
N
procedure 2
procedure 3
procedure 4
NMe2
TMEDA, O2
MeCN, r.t.
Me2N
R3
R2
HN
R3
4 (X = CH2, O)
procedure 1
CuI
R2
N
N
DMI =
R1
N
5
R1
R1
Cu
R3
DMI, O2
MeCN, r.t.
NH3–H2O–EtOH, r.t.
R2
1
2
Me
6
O
HP OR2
OR2
N
N
O
NMI =
7
R1
P
OR2
OR2
NMI, O2
DMF, r.t.
Me
8
Scheme 1 Alkynylation of heteronucleophiles with copper acetylides: a convenient and practical synthesis of ynamides, ynimines, and
alkynylphosphonates
Hetero-substituted alkynes definitely represent the most atom allows these compounds to undergo highly efficient,
useful and versatile class of alkynes.1–4 The strong polar- regio- and stereoselective transformations. Among these
ization of the triple bond due to the presence of the hetero- building blocks, nitrogen- and phosphorus-substituted al-
kynes are emerging as key synthetic intermediates in
chemical synthesis, where their use for the development
of new reactions have resulted in the appearance of new
synthetic paradigms, and also in medicinal chemistry and
material sciences.
SYNTHESIS 2014, 46, 000A–000J
Advanced online publication: 25.03.2014
DOI: 10.1055/s-0033-1341025; Art ID: SS-2014-Z0113-PSP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

B
C. Theunissen et al.
PRACTICAL SYNTHETIC PROCEDURES
As a result of this increased interest for these building cessively washed with aqueous ammonia, water, ethanol,
blocks, there is a strong demand for the development of and diethyl ether, and the resulting bright yellow polymer-
efficient, robust, and reliable methods for their synthesis, ic copper acetylide is finally dried under high vacuum.
which has definitely become a hot topic in modern organ- These bench-stable reagents can be stored at room tem-
ic chemistry. Indeed, a lot of efforts have been recently perature without specific precautions, can be kept for
devoted to the design of straightforward processes that years without noticeable degradation, and – contrary to
would allow for an easy synthesis of nitrogen- (namely certain preconceived ideas – are not explosive at all (in
ynamides)5 and phosphorus-substituted6 alkynes. Despite opposition to copper carbide and bis-copper acetylides).11
the excellent results obtained with these reactions, they,
Due to the operational simplicity, the reaction can be eas-
however, often require heating and/or the presence of a
ily performed on a multigram scale and representative
base – which are not always compatible with the sensitiv-
copper acetylides that can be obtained according to proce-
ity of the products – and the slow addition of one reagent.
dure 1 are shown in Table 1. The reaction is compatible
In addition, they sometimes rely on catalysts or reagents
with alkyl- (Table 1, entries 1–4), alkenyl- (entry 5), and
that are not readily available and their use on large scales
aryl-substituted (entries 6–12) alkynes as well as conju-
can be problematic.
gated ones such as tert-butyl propiolate (entry 13). As a
To address these limitations, we have recently reported a
new approach to nitrogen- and phosphorus-substituted al-
Table 1 Preparation of Copper Acetylidesa
kynes based on the use of readily available reagents, cop-
per acetylides 2.7 These reagents are easily and
procedure 1
conveniently prepared by simple addition of terminal al-
CuI
R1
R1
Cu
kynes 1 to a solution of copper iodide in a mixture of
aqueous ammonia and ethanol followed by filtration of
the copper acetylides 2, which immediately precipitate
from the reaction mixture (Scheme 1).
NH3–H2O–EtOH
r.t., 12 h
1
2
Entry Copper acetylide 2
Yield (%)b Isolated mass
One of the main characteristic features of these polymeric
reagents is their total lack of reactivity. Unlike other org-
anocopper reagents, they are indeed remarkably stable to
acids and air, and their reactions with electrophiles are es-
pecially sluggish (their hydrolysis, which typically re-
quires heating in concentrated hydrochloric acid, is quite
representative of their low reactivity). We have recently
found that they can, however, be readily activated by oxi-
dation with molecular oxygen in the presence of simple
nitrogen ligands such as N,N,N′,N′-tetramethylethylenedi-
amine (TMEDA) or imidazole derivatives, which results
in an umpolung of their reactivity.8 Under these condi-
tions, they can indeed react with various nitrogen and
phosphorus nucleophiles and therefore act as remarkably
practical and efficient alkynylating agents.9 This strategy
could notably be used for the development of efficient en-
tries to ynamides, ynimines, and alkynylphosphonates
(Scheme 1), which can be readily obtained by oxidative
alkynylation of amides/carbamates, imines, and dialkyl
phosphites, respectively, with copper acetylides.
1
2
3
4
2a
2b
2c
2d
86
84
90
55
11.2 g
7.3 g
3.2 g
1.5 g
Cu
Cu
5
Ph
Cu
HO
Cu
Cu
5
2e
2f
2g
2h
2i
54
87
79
91
98
78
1.4 g
13.9 g
3.0 g
1.1 g
16.5 g
1.8 g
Cu
6
F
Cu
7
Br
Cu
8
Cu
9
t-Bu
Cu
10
2j
Scope and Limitations
MeO
Apart from phenylethynylcopper, which is commercially
available, other copper acetylides are readily prepared by
modification of previously reported procedures.10 Upon
addition of a terminal alkyne to a solution of copper(I) io-
dide in a mixture of aqueous ammonia and ethanol, a yel-
low precipitate starts to appear almost instantaneously
(Scheme 1, procedure 1). After 12 hours at room temper-
ature to ensure full metalation of the starting alkyne, the
copper acetylide – which is totally insoluble in all organic
solvents evaluated – is collected by simple filtration, suc-
11
2k
94
7.2 g
Cu
Cu
Cu
12
13
2l
Fe
97
76
1.3 g
2.3 g
t-BuO2C
2m
a Conditions: alkyne (1 equiv), CuI (2 equiv).
b Isolated yield of pure product.
Synthesis 2014, 46, A–J
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Alkynylation of Heteronucleophiles with Copper Acetylides
C
note, more complex copper acetylides that might not be
compatible with the use of ethanol and/or ammonia can be
prepared by an alternative procedure based on the reaction
of the corresponding terminal alkyne with copper(I) io-
dide in the presence of potassium carbonate at room tem-
perature in DMF.9a
Table 2 Synthesis of Ynamides by Alkynylation of γ-Lactam and
Oxazolidin-2-ones with Copper Acetylidesa
procedure 2
O
O
TMEDA, O2
X
X
R1
N
R1
+
Cu
HN
MeCN
r.t., 24–48 h
R3
R3
2
R2
3 (X = CH2, O)
R2
4 (X = CH2, O)
Table 2 illustrates the ability of these reagents to transfer
their alkyne group to various nitrogen nucleophiles such
as γ-lactam and oxazolidin-2-ones 3 (Scheme 1, proce-
dure 2). Previous optimization of the alkynylation of these
nucleophiles with copper acetylides 2 led to conditions in-
volving TMEDA as the ligand in the presence of molecu-
lar oxygen (balloon) in acetonitrile at room temperature
until complete disappearance of the copper acetylide
(which is characterized by complete dissolution to a deep
blue homogeneous reaction mixture after 24–48 h).9a This
reaction has advantages over previously reported ones of
being especially practical (reagent grade acetonitrile and
reagents, room temperature, self-indicating reaction
which changes color upon completion, no workup re-
quired) and conveniently performed on a multigram scale.
Entry Ynamide 4
Yield Isolated
(%)b
mass
O
1
4a
4b
4c
4d
4e
4f
82
12.4 g
N
O
2
92
77
70
61
77
60
91
54
75
1.9 g
0.3 g
3.9 g
1.0 g
0.3 g
0.3 g
2.0 g
0.2 g
0.3 g
N
5
O
Ph
3
N
The reaction readily proceeds regardless the nature of the
copper acetylide, and nitrogen nucleophiles such as γ-lac-
tams (Table 2, entries 1–7) and oxazolidin-2-ones (entries
8–10) are typically transformed to the corresponding yn-
amides 4 in good to excellent yields. Copper acetylides
can also be used for the alkynylation of chiral oxazolidi-
nones, yielding the corresponding chiral ynamides such as
4k with good efficiency (entry 11), provided, however,
that there is no bulky substituent α to the nitrogen atom.
Interestingly, the presence of an aromatic bromide such as
in 4e is compatible with the alkynylation, which provides
a starting point for further functionalization. A limitation
was, however, found in the reactivity of less reactive
amides such as N-methylacetamide and δ-valerolactam,
which showed no reactivity under the reaction conditions.
As a note, an excess (4 equiv) of the nitrogen nucleophile
is used in typical procedure 2. A useful yield of 4d (61%)
is also obtained with a single equivalent of γ-lactam, even
if a higher amount of dimerization of the starting copper
acetylide is observed in this case.
O
4
N
O
5
Br
N
O
6
N
O
MeO
7
4g
4h
4i
N
O
O
8
N
5
O
O
9
F
N
Besides lactams and oxazolidin-2-ones, imines 5 can also
be used as nucleophiles and their alkynylation with copper
acetylides is also quite efficient, especially when the high
sensitivity of the ynimines 6 formed is taken into consid-
eration (Scheme 1, procedure 3). Representative exam-
ples from Table 3 show typical ynimines 6 that can be
obtained using the oxidative alkynylation with copper
acetylides. The procedure is quite similar to the one in-
volving lactams and oxazolidinones, the only difference
being the use of 1,2-dimethylimidazole (DMI) as the li-
gand.9b Diaryl- (Table 3, entry 1) and arylalkylynimines
(entries 2–4) can be obtained with similar efficiency, mix-
tures of E- and Z-isomers being formed in the latter cases.
O
O
10
4j
N
O
O
N
11
4k
72
0.4 g
5
Ph
a Conditions: copper acetylide (1 equiv), lactam or oxazolidinone (4
equiv), TMEDA (1 equiv).
b Isolated yield of pure product.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, A–J

D
C. Theunissen et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 3 Synthesis of Ynimines by Alkynylation of Imines with Cop-
Table 4 Synthesis of Alkynylphosphonates by Alkynylation of Di-
per Acetylidesa
alkyl Phosphites with Copper Acetylidesa
procedure 3
procedure 4
R1
N
HN
R2
O
P
OR2
O
DMI, O2
NMI, O2
R3
R1
R1
OR2
+
Cu
R3
R1
Cu
HP OR2
OR2
+
MeCN
r.t., 12 h
DMF
r.t., 1–12 h
2
R2
2
5
6
8
7
Entry Ynimine 6
Yield Isolated
Entry Alkynylphosphonate 8
Yield
(%)b
Isolated
mass
(%)b
mass
O
N
5
1
2
6a
6b
57
0.2 g
1
8a
92
16.0 g
P
Oi-Pr
Ph
Oi-Pr
Ph
O
N
P
On-Bu
2
3
4
5
6
7
8
8b
8c
8d
8e
8f
92
96
96
88
97
96
48
4.8 g
0.5 g
1.0 g
0.4 g
2.6 g
0.5 g
0.3 g
On-Bu
69
75
0.2 g
O
Cl
Ph
P
OEt
Z/E = 50:50
OEt
O
P
HO
N
On-Bu
On-Bu
3
4
6c
1.5 g
O
P
Oi-Pr
Oi-Pr
Z/E = 40:60
O
N
P
Oi-Pr
Oi-Pr
Fe
O
6d
62
0.2 g
t-Bu
P
OEt
8g
8h
OEt
Z/E = 38:62
O
a Conditions: copper acetylide (1 equiv), imine (4 equiv), 1,2-dimeth-
ylimidazole (2 equiv).
t-BuO2C
P
Oi-Pr
Oi-Pr
b Isolated yield of pure product.
a Conditions: copper acetylide (1 equiv), dialkyl phosphite (4 equiv),
1-methylimidazole (2 equiv).
b Isolated yield of pure product.
In Table 4, the ability to perform a remarkably clean al-
kynylation of dialkyl phosphites 7 yielding to the corre-
sponding alkynylphosphonates
8
is demonstrated
(procedure 4), which further highlights the generality of
the alkynylation of heteronucleophiles with copper
acetylides. This procedure requires the use of DMF as the
solvent and N-methylimidazole (NMI) as the ligand,
which allows for a clean and fast alkynylation of a wide
range of dialkyl phosphites.9a Alkyl- (Table 4, entries 1–
4) and aryl-substituted (entries 6 and 7) alkynylphospho-
nates can conveniently be prepared using the correspond-
ing copper acetylides as well as alkenyl- (entry 5) and
carboxy-substituted (entry 8) ones.
Summary
In summary, we have reported efficient and especially
practical procedures for the alkynylation of nitrogen and
phosphorus nucleophiles based on the alkynylation with
readily available, bench-stable copper acetylides. Yn-
amides, ynimines, and alkynylphosphonates can be readi-
ly obtained at room temperature with the utmost
operational simplicity by the means of these procedures,
which can be easily performed on multigram scales. From
a practical point of view, these ‘practical synthetic proce-
dures’ have many advantages including the use of user-
friendly conditions (room temperature, simple activation
with a balloon of oxygen, self-indicating reaction mixture,
which turns from a yellow heterogeneous suspension to a
Synthesis 2014, 46, A–J
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Alkynylation of Heteronucleophiles with Copper Acetylides
E
Alkynylation of Dialkyl Phosphites with Copper Acetylide; Pro-
cedure 4
homogeneous deep blue or deep green solution upon com-
pletion), the use of reagent grade solvents and reagents,
easy purifications, and they do not rely on expensive li-
gands.
A 5 mL round-bottomed flask was successively charged with dial-
kyl phosphite 7 (8.0 mmol), the copper acetylide 2 (2.0 mmol), and
DMF (4 mL). The resulting bright yellow slurry was then treated
with N-methylimidazole (315 μL, 4.0 mmol) and the reaction mix-
ture was vigorously stirred at r.t. and under an atmosphere of O2
(balloon). After complete disappearance of the alkynylcopper re-
agent (complete dissolution to a deep blue homogeneous reaction
mixture: typically 1–12 h), the reaction was diluted with an aqueous
mixture of sat. aq NH4Cl and 28% NH4OH (1:1 solution, 20 mL)
and extracted with Et2O (3 × 20 mL). The combined organic layers
were washed with brine (20 mL), dried (MgSO4), and concentrated.
The crude residue was finally purified by flash chromatography
over silica gel to give the desired alkynylphosphonate 8.
Procedures
All solvents and starting materials were purchased from commer-
cial suppliers and used without further purification. Petroleum ether
(PE) used refers to the fraction boiling in the 40–60 °C range. Re-
actions were magnetically stirred. Flash chromatography was per-
formed with silica gel 60 (particle size 35–70 μm) supplied by SDS.
Yields refer to chromatographically and spectroscopically pure
compounds. 1H NMR spectra were recorded using an internal deu-
terium lock at ambient temperature on a Bruker 300 MHz spectrom-
eter. Internal references of δH 7.26 was used for CDCl3. Data are
presented as follows: chemical shift (in ppm on the δ scale relative
to Me4Si at 0 ppm), multiplicity (standard abbreviations), coupling
constant (J, in Hz), and integration. Resonances that are either par-
tially or fully obscured are denoted obscured (obs). 13C NMR spec-
tra were recorded at 75 MHz. Internal reference of δC 77.16 ppm
was used for CDCl3. 31P and 19F NMR spectra were recorded at
121/161 and 377 MHz, respectively. Optical rotations were record-
ed on a Perkin Elmer 341 polarimeter at 589 nm and reported as fol-
lows: [α]D20, concentration (c in g/100 mL), and solvent. Melting
points were recorded on a Büchi B-545. IR spectra were recorded
on a Nicolet iS 10 (SMART iTR diamond ATR) spectrophotometer.
High-resolution mass spectra were obtained on a Waters Xevo Qtof
spectrometer. Elemental analyses were obtained by combustion
analysis (for C, H, N) and by inductively coupled plasma atomic
emission spectroscopy (for Cu).
Pent-1-yn-1-ylcopper (2a)
Prepared according to procedure 1 from pent-1-yne (9.9 mL, 100.0
mmol) and a solution of CuI (38.1 g, 200.0 mmol) in a mixture of
NH4OH (28% NH3 solution, 500 mL) and EtOH (300 mL); yield:
11.2 g (86.0 mmol, 86%); bright yellow solid.
Anal. Calcd for C5H7Cu: C, 45.96; H, 5.40; Cu, 47.94. Found: C,
45.36; H, 5.26; Cu, 48.64.
Oct-1-yn-1-ylcopper (2b)
Prepared according to procedure 1 from oct-1-yne (7.4 mL, 50
mmol) and a solution of CuI (19.0 g, 100.0 mmol) in a mixture of
NH4OH (28% NH3 solution, 250 mL) and EtOH (150 mL); yield:
7.3 g (42.0 mmol, 84%); bright yellow solid.
Anal. Calcd for C8H13Cu: C, 55.63; H, 7.59; Cu, 36.79. Found: C,
55.31; H, 7.29; Cu, 36.69.
4-Phenylbut-1-yn-1-ylcopper (2c)
Prepared according to procedure 1 from 4-phenylbut-1-yne (2.6
mL, 18.5 mmol) and a solution of CuI (7.1 g, 37.2 mmol) in a mix-
ture of NH4OH (28% NH3 solution, 100 mL) and EtOH (60 mL);
yield: 3.2 g (16.6 mmol, 90%); bright yellow solid.
Preparation of Copper Acetylides; Procedure 1
To a solution of CuI (3.8 g, 20.0 mmol) in a mixture of NH4OH
(28% NH3 solution, 50 mL) and EtOH (30 mL) was added the al-
kyne 1 (10.0 mmol) dropwise. The deep blue reaction mixture was
stirred overnight at r.t. under argon and the yellow precipitate was
collected by filtration and successively washed with NH4OH (10%
NH3 solution, 3 × 50 mL), H2O (3 × 50 mL), EtOH (3 × 50 mL), and
Et2O (3 × 50 mL). The bright yellow solid was then dried under high
vacuum overnight to afford the desired polymeric copper acetylide
2, which was used without further purification.
Anal. Calcd for C10H9Cu: C, 62.32; H, 4.71; Cu, 32.97. Found: C,
62.10; H, 4.76; Cu, 33.21.
4-Hydroxybut-1-yn-1-ylcopper (2d)
Prepared according to procedure 1 from but-3-yn-1-ol (1.6 mL, 21.1
mmol) and a solution of CuI (8.1 g, 42.5 mmol) in a mixture of
NH4OH (28% NH3 solution, 100 mL) and EtOH (30 mL); yield:
1.54 g (11.6 mmol, 55%); bright yellow solid.
Alkynylation of γ-Lactam and Oxazolidin-2-ones with Copper
Acetylide; Procedure 2
Anal. Calcd for C4H5CuO: C, 36.22; H, 3.80; Cu, 47.91. Found: C,
35.92; H, 3.62; Cu, 48.15.
A 5 mL round-bottomed flask was successively charged with the ni-
trogen nucleophile 3 (8.0 mmol), the copper acetylide 2 (2.0 mmol),
and MeCN (4 mL). The resulting bright yellow slurry was then
treated with TMEDA (300 μL, 2.0 mmol) and the reaction mixture
was vigorously stirred at r.t. and under an atmosphere of O2 (bal-
loon). After complete disappearance of the alkynylcopper reagent
(complete dissolution to a deep blue homogeneous reaction mix-
ture: typically 24–48 h), the crude reaction mixture was concentrat-
ed under vacuum, and the residue was finally purified by flash
chromatography over silica gel to afford the desired ynamide 4.
3-Methylbut-3-en-1-yn-1-ylcopper (2e)
Prepared according to procedure 1 from 2-methylbut-1-en-3-yne
(1.9 mL, 20.0 mmol) and a solution of CuI (7.6 g, 40.0 mmol) in a
mixture of NH4OH (28% NH3 solution, 100 mL) and EtOH (60
mL); yield: 1.4 g (10.9 mmol, 54%); bright yellow solid.
Anal. Calcd for C5H5Cu: C, 46.68; H, 3.92; Cu, 49.40. Found: C,
46.67; H, 3.86; Cu, 48.31.
Phenylethynylcopper (2f)
Alkynylation of Imines with Copper Acetylide; Procedure 3
A 10 mL round-bottomed flask was successively charged with the
imine 5 (8.0 mmol), the copper acetylide 2 (2.0 mmol), and MeCN
(8 mL). The resulting bright yellow slurry was then treated with 1,2-
dimethylimidazole (384 mg, 4.0 mmol) and the reaction mixture
was vigorously stirred at r.t. and under an atmosphere of O2 (bal-
loon). After complete disappearance of the alkynylcopper reagent
(complete dissolution to a deep green homogeneous reaction mix-
ture: typically 12 h), the crude reaction mixture was concentrated
under vacuum and the residue was finally purified by flash chroma-
tography over triethylamine-deactivated silica gel to afford the de-
sired ynimine 6.
Prepared according to procedure 1 from phenylacetylene (10.7 mL,
97.4 mmol) and a solution of CuI (37.3 g, 195.8 mmol) in a mixture
of NH4OH (28% NH3 solution, 500 mL) and EtOH (300 mL); yield:
13.9 g (84.4 mmol, 87%); bright yellow solid.
Anal. Calcd for C8H5Cu: C, 58.35; H, 3.06; Cu, 38.59. Found: C,
58.02; H, 3.08; Cu, 37.99.
(4-Fluorophenyl)ethynylcopper (2g)
Prepared according to procedure 1 from (4-fluorophenyl)ethyne
(2.4 mL, 20.9 mmol) and a solution of CuI (8.0 g, 42.0 mmol) in a
mixture of NH4OH (28% NH3 solution, 100 mL) and EtOH (60
mL); yield: 3.0 g (16.4 mmol, 79%); bright yellow solid.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, A–J

F
C. Theunissen et al.
PRACTICAL SYNTHETIC PROCEDURES
1-(Oct-1-yn-1-yl)pyrrolidin-2-one (4b)
Prepared according to procedure 2 from oct-1-yn-1-ylcopper (2b;
1.85 g, 10.7 mmol), pyrrolidin-2-one (3.3 mL, 43.4 mmol), and
TMEDA (1.6 mL, 10.7 mmol) in MeCN (20 mL). Purified by flash
column chromatography (PE–EtOAc, 50:50); yield: 1.9 g (9.8
mmol, 92%); pale yellow oil.
Anal. Calcd for C8H4FCu: C, 52.60; H, 2.21; Cu, 34.79. Found: C,
52.01; H, 2.19; Cu, 35.13.
(4-Bromophenyl)ethynylcopper (2h)
Prepared according to procedure 1 from (4-bromophenyl)ethyne
(884 mg, 4.9 mmol) and a solution of CuI (1.9 g, 10.0 mmol) in a
mixture of NH4OH (28% NH3 solution, 25 mL) and EtOH (15 mL);
yield: 1.1 g (4.5 mmol, 91%); bright yellow solid.
IR (ATR): 2930, 2857, 2260, 1719, 1399, 1367, 1297, 1218, 1169,
1091, 813, 756 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.57 (t, J = 7.4 Hz, 2 H), 2.33 (t,
J = 8.1 Hz, 2 H), 2.23 (t, J = 7.2 Hz, 2 H), 2.02 (app quint, J = 7.6
Hz, 2 H), 1.44 (app quint, J = 7.2 Hz, 2 H), 1.36–1.12 (m, 6 H), 0.80
(t, J = 7.2 Hz, 3 H).
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.
HRMS (ESI): m/z calcd for C12H20NO [M + H]+: 194.1545; found:
194.1542.
Anal. Calcd for C8H4BrCu: C, 39.45; H, 1.66; Cu, 26.09. Found: C,
40.34; H, 1.76; Cu, 25.19.
4-Tolylethynylcopper (2i)
Prepared according to procedure 1 from 4-tolylethyne (12.0 mL,
94.6 mmol) and a solution of CuI (36.2 g, 190.0 mmol) in a mixture
of NH4OH (28% NH3 solution, 500 mL) and EtOH (300 mL); yield:
16.5 g (92.3 mmol, 98%); bright yellow solid.
Anal. Calcd for C9H7Cu: C, 60.49; H, 3.95; Cu, 35.56. Found:
61.03; H, 4.21; Cu, 36.02.
Characterization data were consistent with those reported in the lit-
erature.12
(4-tert-Butylphenyl)ethynylcopper (2j)
Prepared according to procedure 1 from (4-tert-butylphenyl)ethyne
(1.9 mL, 10.5 mmol) and a solution of CuI (4.0 g, 21.0 mmol) in a
mixture of NH4OH (28% NH3 solution, 50 mL) and EtOH (30 mL);
yield: 1.8 g (8.2 mmol, 78%); bright yellow solid.
1-(4-Phenylbut-1-yn-1-yl)pyrrolidin-2-one (4c)
Prepared according to procedure 2 from 4-phenylbut-1-yn-1-ylcop-
per (2c; 386 mg, 2.0 mmol), pyrrolidin-2-one (610 μL, 8.0 mmol),
and TMEDA (300 μL, 2.0 mmol) in MeCN (4 mL). Purified by
flash column chromatography (cyclohexane–EtOAc, 60:40); yield:
330 mg (1.5 mmol, 77%); orange solid; mp 51 °C.
Anal. Calcd for C12H13Cu: C, 65.28; H, 5.94; Cu, 28.78. Found: C,
64.28; H, 5.84; Cu, 28.01.
IR (ATR): 2257, 1708, 1453, 1394, 1219, 1196, 751, 700 cm–1.
(3-Methoxyphenyl)ethynylcopper (2k)
Prepared according to procedure 1 from (3-methoxyphenyl)ethyne
(5.0 mL, 39.3 mmol) and a solution of CuI (15.0 g, 78.8 mmol) in a
mixture of NH4OH (28% NH3 solution, 200 mL) and EtOH (120
mL); yield: 7.2 g (37.0 mmol, 94%); bright yellow solid.
1H NMR (300 MHz, CDCl3): δ = 7.32–7.17 (m, 5 H), 3.36 (t, J = 7.2
Hz, 2 H), 2.86 (t, J = 7.8 Hz, 2 H), 2.62 (t, J = 7.2 Hz, 2 H), 2.41 (t,
J = 8.4 Hz, 2 H), 2.09 (quint, J = 7.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 176.2, 140.8, 128.6, 128.5, 126.4,
72.2, 72.0, 50.1, 35.5, 29.7, 21.0, 18.8.
Anal. Calcd for C9H7CuO: C, 55.52; H, 3.62; Cu, 32.64. Found: C,
55.37; H, 3.40; Cu, 31.98.
HRMS (ESI): m/z calcd for C14H16NO [M + H]+: 214.1232; found:
Ferrocenylethynylcopper (2l)
214.1233.
Prepared according to procedure 1 from ethynylferrocene (1.0 g, 4.8
mmol) and a solution of CuI (1.8 g, 9.6 mmol) in a mixture of
NH4OH (28% NH3 solution, 25 mL) and EtOH (15 mL); yield: 1.3
g (4.7 mmol, 97%); bright orange solid.
Characterization data were consistent with those reported in the lit-
erature.13
1-(Phenylethynyl)pyrrolidin-2-one (4d)
Prepared according to procedure 2 from phenylethynylcopper (2f;
5.0 g, 30.4 mmol), pyrrolidin-2-one (9.2 mL, 121.1 mmol), and
TMEDA (4.6 mL, 30.7 mmol) in MeCN (60 mL). Purified by flash
column chromatography (PE–EtOAc, 50:50); yield: 3.9 g (21.1
mmol, 70%); pale yellow solid; mp 52 °C.
Anal. Calcd for C12H9CuFe: C, 52.87; H, 3.33; Cu, 23.31. Found: C,
53.02; H, 3.18; Cu, 22.97.
(tert-Butoxycarbonyl)ethynylcopper (2m)
Prepared according to procedure 1 from tert-butyl propiolate (2.2
mL, 16.0 mmol) and a solution of CuI (6.1 g, 32.0 mmol) in a mix-
ture of NH4OH (28% NH3 solution, 160 mL) and EtOH (50 mL);
yield: 2.3 g (12.2 mmol, 76%); bright orange solid.
IR (ATR): 2243, 1717, 1488, 1392, 1198, 1150, 757, 696, 647 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.46–7.38 (m, 2 H), 7.30–7.23 (m,
3 H), 3.76 (t, J = 7.3 Hz, 2 H), 2.46 (t, J = 8.0 Hz, 2 H), 2.15 (app
quint, J = 7.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 175.9, 131.6, 128.3, 128.0, 122.7,
80.5, 72.7, 50.2, 29.8, 19.0.
Anal. Calcd for C7H9CuO2: C, 44.56; H, 4.81; Cu, 33.68. Found: C,
44.79; H, 4.67; Cu, 33.21.
1-(Pent-1-yn-1-yl)pyrrolidin-2-one (4a)
Prepared according to procedure 2 from pent-1-yn-1-ylcopper (2a;
13.1 g, 100.2 mmol), pyrrolidin-2-one (30.5 mL, 401.4 mmol), and
TMEDA (15.0 mL, 100.0 mmol) in MeCN (200 mL). Purified by
flash column chromatography (PE–EtOAc, 50:50); yield: 12.4 g
(82.0 mmol, 82%); pale yellow oil.
HRMS (ESI): m/z calcd for C12H12NO [M + H]+: 186.0919; found:
186.0921.
Characterization data were consistent with those reported in the lit-
erature.5c
IR (ATR): 2963, 2261, 1716, 1390, 1298, 1211, 1089, 639 cm–1.
1-(4-Bromophenylethynyl)pyrrolidin-2-one (4e)
1H NMR (300 MHz, CDCl3): δ = 3.60 (t, J = 7.5 Hz, 2 H), 2.36 (t,
J = 8.1 Hz, 2 H), 2.25 (t, J = 7.2 Hz, 2 H), 2.10–1.95 (m, 2 H), 1.53–
1.46 (m, 2 H), 0.92 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 176.1, 72.4, 71.5, 50.1, 29.6, 22.3,
20.5, 18.6, 13.4.
HRMS (ESI): m/z calcd for C9H14NO [M + H]+: 152.1076; found:
152.1075.
Prepared according to procedure 2 from (4-bromophenyl)ethynyl-
copper (2h; 1.5 g, 6.2 mmol), pyrrolidin-2-one (1.9 mL, 25.0
mmol), and TMEDA (930 μL, 6.2 mmol) in MeCN (12 mL). Puri-
fied by flash column chromatography (PE–EtOAc, 60:40); yield:
992 mg (3.8 mmol, 61%); white solid; mp 88 °C.
IR (ATR): 2986, 2900, 2237, 1720, 1400, 1207, 1144, 1073 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.38 (d, J = 10.2 Hz, 2 H), 7.25 (d,
J = 9.0 Hz, 2 H), 3.72 (t, J = 7.2 Hz, 2 H), 2.43 (t, J = 8.4 Hz, 2 H),
2.18–2.07 (m, 2 H).
Synthesis 2014, 46, A–J
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Alkynylation of Heteronucleophiles with Copper Acetylides
G
13C NMR (75 MHz, CDCl3): δ = 176.1, 133.2, 131.8, 122.3, 121.9,
81.8, 72.0, 50.3, 30.0, 19.2.
1H NMR (300 MHz, CDCl3): δ = 7.45–7.38 (m, 2 H), 7.04–6.95 (m,
2 H), 4.48 (dd, J = 9.3, 7.7 Hz, 2 H), 4.00 (dd, J = 9.3, 7.7 Hz, 2 H).
HRMS (ESI): m/z calcd for C12H11BrNO [M + H]+: 264.0029;
found: 264.0024.
13C NMR (75 MHz, CDCl3): δ = 162.6 (d, J = 248 Hz), 156.0, 133.8
(d, J = 8.4 Hz), 118.3 (d, J = 3.5 Hz), 115.7 (d, J = 21.9 Hz), 78.7,
70.3, 63.2, 47.1.
19F NMR (377 MHz, CDCl3): δ = –114.1 (s, 1 F).
HRMS (ESI): m/z calcd for C11H9FNO2 [M + H]+: 206.0617; found:
1-(4-Tolylethynyl)pyrrolidin-2-one (4f)
Prepared according to procedure 2 from 4-tolylethynylcopper (2i;
357 mg, 2.0 mmol), pyrrolidin-2-one (610 μL, 8.0 mmol), and
TMEDA (300 μL, 2.0 mmol) in MeCN (4 mL). Purified by flash
column chromatography (cyclohexane–EtOAc, 60:40); yield: 306
mg (1.5 mmol, 77%); white solid; mp 115 °C.
206.0618.
Characterization data were consistent with those reported in the lit-
erature.16
IR (ATR): 2246, 1713, 1402, 1233, 1199, 1150, 813 cm–1.
3-(4-Tolylethynyl)oxazolidin-2-one (4j)
1H NMR (300 MHz, CDCl3): δ = 7.33 (d, J = 8.1 Hz, 2 H), 7.10 (d,
J = 7.8 Hz, 2 H), 3.77 (t, J = 7.2 Hz, 2 H), 2.48 (t, J = 8.4 Hz, 2 H),
2.32 (s, 3 H), 2.16 (app quint, J = 7.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 175.9, 138.1, 131.6, 129.1, 119.6,
79.8, 72.7, 50.3, 29.8, 21.6, 19.0.
Prepared according to procedure 2 from 4-tolylethynylcopper (2i;
357 mg, 2 mmol), oxazolidin-2-one (696 mg, 8 mmol), and
TMEDA (300 μL, 2 mmol) in MeCN (4 mL). Purified by flash col-
umn chromatography (cyclohexane–EtOAc, 60:40); yield: 304 mg
(1.5 mmol, 75%); white solid; mp 123 °C.
HRMS (ESI): m/z calcd for C13H14NO [M + H]+: 200.1075; found:
200.1077.
IR (ATR): 2263, 1752, 1417, 1217, 1199, 1164, 1031, 818, 746,
707 cm–1.
Characterization data were consistent with those reported in the lit-
erature.14
1H NMR (300 MHz, CDCl3): δ = 7.33 (d, J = 8.1 Hz, 2 H), 7.11 (d,
J = 7.8 Hz, 2 H), 4.47 (dd, J = 9.3, 7.7 Hz, 2 H), 3.99 (dd, J = 9.3,
7.7 Hz, 2 H), 2.34 (s, 3 H).
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.
HRMS (ESI): m/z calcd for C12H12NO2 [M + H]+: 202.0868; found:
202.0870.
1-(3-Methoxyphenylethynyl)pyrrolidin-2-one (4g)
Prepared according to procedure
2 from (3-methoxyphe-
nyl)ethynylcopper (2k; 390 mg, 2.0 mmol), pyrrolidin-2-one (610
μL, 8.0 mmol), and TMEDA (300 μL, 2.0 mmol) in MeCN (4 mL).
Purified by flash column chromatography (cyclohexane–EtOAc,
60:40); yield: 260 mg (1.2 mmol, 60%); orange oil.
Characterization data were consistent with those reported in the lit-
erature.5f
IR (ATR): 2962, 2247, 1596, 1574, 1424, 1392, 1197, 1135, 1034,
784, 689 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.17 (t, J = 7.8 Hz, 1 H), 7.01 (d,
J = 7.5 Hz, 1 H), 6.95 (s, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 3.76 (s, 3
H), 3.75 (obs t, J = 7.5 Hz, 2 H), 2.45 (t, J = 8.1 Hz, 2 H), 2.18 (app
quint, J = 7.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 175.7, 159.2, 129.2, 123.9, 123.6,
116.1, 114.5, 80.4, 72.5, 55.2, 50.1, 29.6, 18.8.
HRMS (ESI): m/z calcd for C13H14NO2 [M + H]+: 216.1025; found:
216.1024.
(4S,5R)-4-Methyl-3-(oct-1-yn-1-yl)-5-phenyloxazolidin-2-one
(4k)
Prepared according to procedure 2 from oct-1-yn-1-ylcopper (2b;
340 mg, 2.0 mmol), (4S,5R)-4-methyl-5-phenyloxazolidin-2-one
(1.42 g, 8.0 mmol), and TMEDA (300 μL, 2.0 mmol) in MeCN (4
mL). Purified by flash column chromatography (PE–EtOAc,
20
90:10); yield: 411 mg (1.45 mmol, 72%); sticky colorless oil; [α]D
–6 (c 1.0, CHCl3).
IR (ATR): 2931, 2253, 1760, 1405, 1188, 1125 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.34 (m, 3 H), 7.27–7.23 (m,
2 H), 5.68 (d, J = 8.1 Hz, 1 H), 4.29 (dq, J = 8.1, 6.6 Hz, 1 H), 2.31
(t, J = 6.9 Hz, 2 H), 1.57–1.47 (m, 2 H), 1.41–1.26 (m, 6 H), 0.90 (t,
J = 6.6 Hz, 3 H), 0.87 (t, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 156.1, 134.2, 128.9, 128.7, 126.0,
79.5, 72.3, 69.1, 58.1, 31.3, 28.8, 28.6, 22.6, 18.5, 14.8, 14.0.
3-(Oct-1-yn-1-yl)oxazolidin-2-one (4h)
Prepared according to procedure 2 from oct-1-yn-1-ylcopper (2b;
1.9 g, 11.2 mmol), oxazolidin-2-one (3.9 g, 44.8 mmol), and
TMEDA (1.7 mL, 11.3 mmol) in MeCN (22 mL). Purified by flash
column chromatography (PE–EtOAc, 60:40); yield: 2.0 g (10.2
mmol, 91%); pale yellow oil.
IR (ATR): 2929, 2858, 2269, 1767, 1415, 1301, 1206, 1115, 1035,
976, 751 cm–1.
HRMS (ESI): m/z calcd for C18H24NO2 [M + H]+: 286.1807; found:
286.1809.
1H NMR (300 MHz, CDCl3): δ = 4.39 (dd, J = 9.1, 7.7 Hz, 2 H),
3.86 (dd, J = 9.3, 7.8 Hz, 2 H), 2.28 (t, J = 7.0 Hz, 2 H), 1.72–1.17
(m, 8 H), 0.87 (t, J = 6.3 Hz, 3 H).
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.
HRMS (ESI): m/z calcd for C11H18NO2 [M + H]+: 196.1338; found:
196.1341.
N-(Diphenylmethylene)oct-1-yn-1-amine (6a)
Prepared according to procedure 3 from oct-1-yn-1-ylcopper (2b;
173 mg, 1.00 mmol), diphenylmethanimine (670 μL, 4.00 mmol),
and 1,2-dimethylimidazole (175 μL, 1.97 mmol) in MeCN (4 mL).
Purified by flash column chromatography [on triethylamine-deacti-
vated silica gel, PE–Et2O (95:5). Note: the column had to be run
quickly as the compound is rather sensitive to silica gel]; yield: 165
mg (0.57 mmol, 57%); pale orange oil.
Characterization data were consistent with those reported in the lit-
erature.15
IR (ATR): 2919, 2848, 2246, 1661, 1444, 1313, 1274, 761, 692, 638
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.73 (d, J = 7.5 Hz, 2 H), 7.48–
7.44 (m, 6 H), 7.40–7.35 (m, 2 H), 2.43 (t, J = 6.8 Hz, 2 H), 1.45–
140 (m, 2 H), 1.31–1.23 (m, 6 H), 0.88 (t, J = 9.6 Hz, 3 H).
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.
3-(4-Fluorophenylethynyl)oxazolidin-2-one (4i)
Prepared according to procedure 2 from (4-fluorophenyl)ethynyl-
copper (2g; 365 mg, 2.0 mmol), oxazolidin-2-one (696 mg, 8.0
mmol), and TMEDA (300 μL, 2.0 mmol) in MeCN (4 mL). Purified
by flash column chromatography (cyclohexane–EtOAc, 60:40);
yield: 221 mg (1.1 mmol, 54%); white solid; mp 114 °C.
IR (ATR): 2268, 1754, 1416, 1208, 1195, 1165, 1091, 835, 744 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, A–J

H
C. Theunissen et al.
PRACTICAL SYNTHETIC PROCEDURES
HRMS (ESI): m/z calcd for C21H24N [M + H]+: 290.1909; found:
290.1902.
IR (ATR): 2955, 2927, 2870, 2361, 2341, 2189, 1576, 1456, 1411,
1383, 1264, 1105, 1069, 1023, 1000, 887, 816, 782, 752, 724, 492
cm–1.
N-[1-(2-Chlorophenyl)pentylidene]pent-1-yn-1-amine (6b)
Obtained as a mixture of Z- and E-isomers in a 50:50 ratio. Prepared
according to procedure 3 from pent-1-yn-1-ylcopper (2a; 131 mg,
1.00 mmol), 1-(2-chlorophenyl)pentan-1-imine (783 mg, 4.00
mmol), and 1,2-dimethylimidazole (175 μL, 1.97 mmol) in MeCN
(4 mL). Purified by flash column chromatography [on triethyl-
amine-deactivated silica gel, PE–Et2O (95:5). Note: the column had
to be run quickly as the compound is rather sensitive to silica gel];
yield: 180 mg (0.69 mmol, 69%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ (major) = 7.24–7.12 (m, 2 H), 6.99
(d, J = 7.1 Hz, 1 H), 4.16 (s, 2 H), 4.14 (s, 2 H), 4.02 (s, 5 H), 2.74
(t, J = 7.6 Hz, 2 H), 2.41 (s, 3 H), 2.27 (s, 3 H), 1.70 (app quint, J =
7.5 Hz, 2 H), 1.46 (app sext, J = 7.4 Hz, 2 H), 0.98 (t, J = 7.3 Hz, 3
H); δ (minor) = 7.24–7.12 (m, 3 H), 4.49 (s, 2 H), 4.30 (s, 2 H), 4.27
(s, 5 H), 3.03 (t, J = 7.7 Hz, 2 H), 2.35 (s, 6 H), 1.63 (app quint, J =
7.5 Hz, 2 H), 1.46 (app sext, J = 7.4 Hz, 2 H), 1.00 (t, J = 7.2 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ (major) = 185.8, 140.5, 137.2,
132.7, 130.2, 125.6, 123.1, 87.6, 87.1, 71.1, 69.8, 68.6, 66.6, 41.0,
28.1, 22.6, 20.4, 16.7, 14.0; δ (minor) = 185.7, 139.9, 137.9, 134.3,
130.7, 125.4, 125.3, 93.2, 86.4, 71.4, 69.9, 69.0, 66.8, 38.4, 28.4,
23.0, 20.6, 17.0, 13.9.
IR (ATR): 2958, 2929, 2866, 2207, 1590, 1467, 1429, 1340, 1182,
1033, 745.
1H NMR (300 MHz, CDCl3): δ = 7.43–7.39 and 7.17–7.13 (m, 1 H,
stereoisomers), 7.36–7.27 (m, 3 H), 3.06 and 2.72 (t, J = 7.5 Hz, t,
J = 7.4 Hz, 2 H, stereoisomers), 2.57 and 2.24 (t, J = 6.9 Hz, t, J =
6.8 Hz 2 H, stereoisomers), 1.68–1.61 (m, 2 H), 1.52–1.28 (m, 4 H),
1.06 and 0.73 (t, J = 7.3 Hz, t, J = 7.3 Hz, 3 H, stereoisomers), 0.92
and 0.89 (t, J = 7.3 Hz, t, J = 7.2 Hz, 3 H, stereoisomers).
13C NMR (75 MHz, CDCl3): δ = 184.3 and 181.8 (stereoisomers),
138.8 and 138.7 (stereoisomers), 131.7, 130.3, 130.0, 129.8, 129.7,
129.6 and 127.7 (stereoisomers), 126.7 and 126.6 (stereoisomers),
96.3 and 90.1 (stereoisomers), 82.1 and 81.4 (stereoisomers), 39.8
and 36.4 (stereoisomers), 28.1 and 27.9 (stereoisomers), 22.7, 22.6,
22.4, 22.3, 22.1 and 21.5 (stereoisomers) 13.9, 13.7, 13.6 and 13.1
(stereoisomers).
HRMS (ESI): m/z calcd for C25H27FeN [M]+: 397.1493; found:
397.1509.
Diisopropyl (Pent-1-yn-1-yl)phosphonate (8a)
Prepared according to procedure 4 from pent-1-yn-1-ylcopper (2a;
9.8 g, 75.0 mmol), diisopropyl phosphite (50.3 mL, 300.0 mmol),
and N-methylimidazole (12.0 mL, 150.5 mmol) in DMF (150 mL).
Purified by flash column chromatography (pentane–EtOAc, 50:50);
yield: 16.0 g (68.9 mmol, 92%); colorless oil.
IR (ATR): 2982, 2205, 1385, 1255, 981 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.67–4.60 (m, 2 H), 2.24 (td, J =
6.9 Hz and JH,P = 4.2 Hz, 2 H), 1.53 (tq, J = 7.5, 7.2 Hz, 2 H), 1.28
(d, J = 7.2 Hz, 12 H), 0.93 (t, J = 6.6 Hz, 3 H).
HRMS (ESI): m/z calcd for C16H21ClN [M + H]+: 262.1363; found:
262.1365.
N-[1-(2,3-Dimethylphenyl)pentylidene]pentyn-1-yn-1-amine
(6c)
13C NMR (75 MHz, CDCl3): δ = 102.1 (d, JC,P = 52.5 Hz), 72.2 (d,
J
C,P = 300.0 Hz), 72.0 (d, JC,P = 5.3 Hz), 24.4 (d, JC,P = 4.5 Hz), 23.7
Obtained as a mixture of Z- and E-isomers in a 40:60 ratio. Prepared
according to procedure 3 from pent-1-yn-1-ylcopper (2a; 1.0 g, 7.6
mmol), 1-(2,3-dimethylphenyl)pentan-1-imine (5.8 g, 30.6 mmol),
and 1,2-dimethylimidazole (1.35 mL, 15.2 mmol) in MeCN (30
mL). Purified by flash column chromatography [on triethylamine-
deactivated silica gel, PE–Et2O (95:5). Note: the column had to be
run quickly as the compound is rather sensitive to silica gel]; yield:
1.45 g (5.7 mmol, 75%); pale yellow oil.
(d, JC,P = 4.8 Hz), 21.3, 21.2, 13.3.
31P NMR (121 MHz, CDCl3): δ = –8.7.
HRMS (ESI): m/z calcd for C11H22O3P [M + H]+: 233.1307; found:
233.1305.
Dibutyl (Pent-1-yn-1-yl)phosphonate (8b)
Prepared according to procedure 4 from pent-1-yn-1-ylcopper (2a;
2.6 g, 20.0 mmol), dibutyl phosphite (15.7 mL, 80.0 mmol), and N-
methylimidazole (3.2 mL, 4.0 mmol) in DMF (40 mL). Purified by
flash column chromatography (cyclohexane–EtOAc, 60:40); yield:
4.8 g (18.4 mmol, 92%); pale yellow oil.
IR (ATR): 2958, 2929, 2871, 2361, 2341, 1597, 1456, 1378, 1337,
1274, 1177, 1087, 1017, 989, 784, 749, 722 cm–1.
1H NMR (300 MHz, CDCl3): δ (major) = 7.17–7.06 (m, 2 H), 6.90–
6.86 (m, 1 H), 2.65 (t, J = 7.5 Hz, 2 H), 2.29 (s, 3 H), 2.22 (t, J = 6.8
Hz, 2 H), 2.13 (s, 3 H), 1.66–1.58 (m, 2 H), 1.56–1.26 (m, 4 H), 0.91
(t, J = 7.3 Hz, 3 H), 0.69 (t, J = 7.3 Hz, 3 H); δ (minor ) = 7.17–7.06
(m, 3 H), 2.92 (t, J = 7.6 Hz, 2 H), 2.55 (t, J = 6.9 Hz, 2 H), 2.13 (s,
3 H), 2.25 (s, 3 H), 1.66–1.58 (m, 2 H), 1.56–1.26 (m, 4 H), 1.05 (t,
J = 7.3 Hz, 3 H), 0.89 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ (major) = 186.2, 140.2, 137.3, 132.7,
130.0, 125.5, 123.2, 88.8, 82.7, 41.1, 28.1, 22.7, 22.6, 21.7, 20.4,
16.6, 14.0, 13.1; δ (minor) = 187.1, 140.0, 137.8, 134.2, 130.5,
125.4, 125.3, 94.1, 81.8, 38.1, 28.3, 23.0, 22.9, 22.2, 20.6, 16.9,
13.9, 13.7.
IR (ATR): 2961, 2204, 1272, 1063, 1022, 992, 794 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.05 (app q, J = 7.6 Hz, 4 H), 2.30
(td, J = 7.0 Hz and JH,P = 4.3 Hz, 2 H), 1.73–1.52 (m, 6 H), 1.41 (app
sext, J = 7.6 Hz, 4 H), 1.00 (t, J = 7.3 Hz, 3 H), 0.92 (t, J = 7.6 Hz,
6 H).
13C NMR (75 MHz, CDCl3): δ = 103.0 (d, JC,P = 52.4 Hz), 70.7 (d,
JC,P = 300.6 Hz), 66.7 (d, JC,P = 5.6 Hz), 32.3 (d, JC,P = 7.3 Hz), 21.2
(d, JC,P = 4.4 Hz), 21.1 (d, JC,P = 2.3 Hz), 18.8, 13.7, 13.5.
31P NMR (161 MHz, CDCl3): δ = –5.1.
HRMS (ESI): m/z calcd for C13H26O3P [M + H]+: 261.1620; found:
HRMS (ESI): m/z calcd for C18H26N [M + H]+: 256.2065; found:
256.2065.
261.1617.
Diethyl (4-Phenylbut-1-yn-1-yl)phosphonate (8c)
N-[1-(2,3-Dimethylphenyl)pentylidene](ferrocenylethynyl)-1-
amine (6d)
Prepared according to procedure 4 from 4-phenylbut-1-yn-1-ylcop-
per (2c; 385 mg, 2.0 mmol), diethyl phosphite (1.0 mL, 8.0 mmol),
and N-methylimidazole (320 μL, 4.0 mmol) in DMF (4 mL). Puri-
fied by flash column chromatography (cyclohexane–EtOAc,
50:50); yield: 513 mg (1.93 mmol, 96%); pale yellow oil.
Obtained as a mixture of Z- and E-isomers in a 38:62 ratio. Prepared
according to procedure 3 from ferrocenylethynylcopper (2l; 273 g,
1.00 mmol), 1-(2,3-dimethylphenyl)pentan-1-imine (757 m g, 4.00
mmol), and 1,2-dimethylimidazole (175 μL, 1.97 mmol) in MeCN
(4 mL). Purified by flash column chromatography [on triethyl-
amine-deactivated silica gel, PE–EtOAc (90:10). Note: the column
had to be run quickly as the compound is rather sensitive to silica
gel]; yield: 246 mg (0.62 mmol, 62%); pale orange oil.
IR (ATR): 2984, 2204, 1262, 1022, 974, 752 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.29–7.22 (m, 2 H), 7.21–7.13 (m,
3 H), 4.08–3.95 (m, 4 H), 2.84 (t, J = 7.3 Hz, 2 H), 2.60 (td, J = 7.3
Hz and JH,P = 4.3 Hz, 2 H), 1.27 (t, J = 7.1 Hz, 6 H).
Synthesis 2014, 46, A–J
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Alkynylation of Heteronucleophiles with Copper Acetylides
I
13C NMR (75 MHz, CDCl3): δ = 139.3, 128.4, 128.3, 126.6, 101.9
(d, JC,P = 52.1 Hz), 71.2 (d, JC,P = 298.6 Hz), 62.9 (d, JC,P = 5.4 Hz),
33.5 (d, JC,P = 2.1 Hz), 21.2 (d, JC,P = 4.5 Hz), 16.0 (d, JC,P = 7.2 Hz).
mL, 8.0 mmol), and N-methylimidazole (320 μL, 4.0 mmol) in
DMF (4 mL). Purified by flash column chromatography (cyclohex-
ane–EtOAc, 50:50); yield: 563 mg (1.91 mmol, 96%); colorless oil.
31P NMR (161 MHz, CDCl3): δ = –5.8.
IR (ATR): 2965, 2185, 1264, 1023, 974, 865, 755 cm–1.
HRMS (ESI): m/z calcd for C14H20O3P [M + H]+: 267.1150; found:
267.1147.
1H NMR (300 MHz, CDCl3): δ = 7.50 (d, J = 8.4 Hz, 2 H), 7.38 (d,
J = 8.5 Hz, 2 H), 4.22 (m, 4 H), 1.40 (t, J = 7.0 Hz, 6 H), 1.31 (s, 9
H).
Dibutyl (4-Hydroxybut-1-yn-1-yl)phosphonate (8d)
13C NMR (75 MHz, CDCl3): δ = 154.8, 132.9 (d, JC,P = 2.4 Hz),
126.0, 116.8 (d, JC,P = 5.6 Hz), 100.0 (d, JC,P = 52.9 Hz), 78.1 (d,
Prepared according to procedure 4 from 4-hydroxybut-1-yn-1-yl-
copper (2d; 530 mg, 4.0 mmol), dibutyl phosphite (3.1 mL, 16.0
mmol), and N-methylimidazole (640 μL, 8.0 mmol) in DMF (8
mL). Purified by flash column chromatography (cyclohexane–
EtOAc, 10:90); yield: 1.0 g (3.81 mmol, 96%); colorless oil.
J
C,P = 298.7 Hz), 63.5 (d, JC, P = 5.4 Hz), 35.4, 31.2, 16.5 (d, JC,P =
6.9 Hz).
31P NMR (121 MHz, CDCl3): δ = –5.1.
IR (ATR): 2961, 2206, 1250, 1058, 1023, 731 cm–1.
HRMS (ESI): m/z calcd for C16H23O3P + Na [M + Na]+: 317.1283;
1H NMR (300 MHz, CDCl3): δ = 4.06 (app q, J = 7.3 Hz, 4 H), 3.79
found: 317.1280.
(t, J = 6.4 Hz, 2 H), 2.74 (br s, 1 H), 2.61 (td, J = 7.3 Hz and JH,P
4.4 Hz, 2 H), 1.68 (app quint, J = 6.9 Hz, 4 H), 1.42 (app sext, J =
7.7 Hz, 4 H), 0.93 (t, J = 7.4 Hz, 6 H).
=
Characterization data were consistent with those reported in the lit-
erature.17
Diisopropyl (tert-Butoxycarbonylethynyl)phosphonate (8h)
Prepared according to procedure 4 from (tert-butoxycarbon-
yl)ethynylcopper (2m; 377 mg, 2.0 mmol), diisopropyl phosphite
(1.35 mL, 8.0 mmol), and N-methylimidazole (320 μL, 4.0 mmol)
in DMF (4 mL). Purified by flash column chromatography (pen-
tane–EtOAc, 50:50); yield: 279 mg (0.96 mmol, 48%); brownish
orange oil.
13C NMR (75 MHz, CDCl3): δ = 100.9 (d, JC,P = 52.6 Hz), 71.1 (d,
J
C,P = 300.1 Hz), 66.8 (d, JC,P = 6.0 Hz), 59.7, 32.1 (d, JC,P = 7.2 Hz),
23.4 (d, JC,P = 4.3 Hz), 18.6, 13.5.
31P NMR (161 MHz, CDCl3): δ = –5.4.
HRMS (ESI): m/z calcd for C12H24O4P [M + H]+: 263.1412; found:
263.1355.
IR (ATR): 2975, 1708, 1369, 1255, 1151, 983 cm–1.
Diisopropyl (3-Methylbut-3-en-1-yn-1-yl)phosphonate (8e)
Prepared according to procedure 4 from 3-methylbut-3-en-1-yn-1-
ylcopper (2e; 257 mg, 2.0 mmol), diisopropyl phosphite (1.35 mL,
8.0 mmol), and N-methylimidazole (320 μL, 4.0 mmol) in DMF (4
mL). Purified by flash column chromatography (pentane–EtOAc,
60:40); yield: 405 mg (1.75 mmol, 88%); colorless oil.
1H NMR (300 MHz, CDCl3): δ = 4.67–4.60 (m, 2 H), 1.38 (s, 9 H),
1.26 (d, J = 6.3 Hz, 12 H).
13C NMR (75 MHz, CDCl3): δ = 150.6, 87.4 (d, JC,P = 45.8 Hz),
85.4, 74.0 (d, JC,P = 285.0 Hz), 73.4 (d, JC,P = 5.3 Hz), 28.0, 23.9 (d,
J
C,P = 4.5 Hz), 23.6 (d, JC,P = 4.9 Hz).
IR (ATR): 2979, 2182, 1377, 1258, 983 cm–1.
31P NMR (121 MHz, CDCl3): δ = –11.6.
1H NMR (300 MHz, CDCl3): δ = 5.45 (br s, 1 H), 5.39 (br s, 1 H),
4.67–4.59 (m, 2 H), 1.81 (s, 3 H), 1.26 (d, J = 6.3 Hz, 12 H).
HRMS (ESI): m/z calcd for C13H24O5P [M + H]+: 291.1361; found:
291.1359.
13C NMR (75 MHz, CDCl3): δ = 127.5, 124.5, 99.3 (d, JC,P = 51.8
Hz), 78.8 (d, JC,P = 300.0 Hz), 72.2 (d, JC,P = 6.0 Hz), 23.9 (d, JC,P
4.5 Hz), 23.7 (d, JC,P = 4.8 Hz), 22.1.
=
Acknowledgment
31P NMR (121 MHz, CDCl3): δ = –8.6.
HRMS (ESI): m/z calcd for C11H20O3P [M + H]+: 231.1150; found:
Our work was supported by the Université Libre de Bruxelles, the
Université de Versailles Saint-Quentin-en-Yvelines, the CNRS, the
CMCU/PHC Utique (grant 10G1025), the ANR (grant DYNAMITE
ANR-2010-BLAN-704), and the FNRS (Incentive Grant for Scien-
tific Research n° F.4530.13). CT, ML, KJ, and CG, respectively,
acknowledge the Fonds pour la formation à la Recherche dans l’In-
dustrie et dans l’Agriculture (F.R.I.A.), the Ministère de la Recher-
che, and the Université Libre de Bruxelles for graduate fellowships.
231.1145.
Diisopropyl Phenylethynylphosphonate (8f)
Prepared according to procedure 4 from phenylethynylcopper (2f;
1.7 g, 10.3 mmol), diisopropyl phosphite (6.9 mL, 41.1 mmol), and
N-methylimidazole (1.6 mL, 20.1 mmol) in DMF (20 mL). Purified
by flash column chromatography (pentane–EtOAc, 50:50); yield:
2.65 g (9.95 mmol, 97%); colorless oil.
Supporting Information for this article is available online at
IR (ATR): 2981, 2186, 1386, 1261, 988, 851, 758 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.52 (d, J = 7.0 Hz, 2 H), 7.46–
7.31 (m, 3 H), 4.88–4.71 (m, 2 H), 1.38 (d, J = 6.3 Hz, 12 H).
13C NMR (75 MHz, CDCl3): δ = 132.6 (d, JC,P = 2.5 Hz), 130.6,
128.6, 119.7 (d, JC,P = 35.9 Hz), 98.2 (d, JC,P = 52.5 Hz), 79.9 (d,
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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Synthesis 2014, 46, A–J
© Georg Thieme Verlag Stuttgart · New York