Expanding the oxidative chemistry of organocopper reagents: Facile oxidative cross-coupling of copper acetylides with arylboronic acids

Article abstract of DOI:10.1007/s00706-012-0896-0

We have developed an efficient procedure for oxidative cross-coupling between arylboronic acids and alkynylcopper reagents. Upon simple addition of 1,10-phenanthroline in the presence of oxygen, these highly stable, readily available polymeric reagents are easily activated and transfer their alkynyl group after subsequent transmetallation with the boronic acid. These results further expand the oxidative chemistry of organocopper compounds together with providing a user-friendly entry to diaryl acetylenes.

Full text of DOI:10.1007/s00706-012-0896-0

Monatsh Chem (2013) 144:523–529
DOI 10.1007/s00706-012-0896-0
ORIGINAL PAPER
Expanding the oxidative chemistry of organocopper reagents:
facile oxidative cross-coupling of copper acetylides
with arylboronic acids
Florian Verna
Gwilherm Evano
•
C e´ line Guissart
•
Jonathan Pous
•
Received: 5 October 2012 / Accepted: 29 November 2012 / Published online: 1 February 2013
Ó Springer-Verlag Wien 2013
Abstract We have developed an efficient procedure for
oxidative cross-coupling between arylboronic acids and
alkynylcopper reagents. Upon simple addition of 1,10-
phenanthroline in the presence of oxygen, these highly
stable, readily available polymeric reagents are easily
activated and transfer their alkynyl group after subsequent
transmetallation with the boronic acid. These results further
expand the oxidative chemistry of organocopper com-
pounds together with providing a user-friendly entry to
diaryl acetylenes.
[4–6], the synthetic potential of the oxidative chemistry of
organocopper reagents was realized only later on [7, 8].
Remarkable work by Lipshutz [9], Knochel [10], and
Spring [11–13] demonstrated the efficiency of such pro-
cedures, notably for the formation of carbon–carbon bonds
in biaryls, dienes, and aromatic alkynes, all these reactions
being based on the formation of an organocuprate followed
by its oxidation (Scheme 1, Eqs. 1 and 2). Besides the
development of efficient procedures for the formation of a
wide range of C–C bonds based on the oxidation of orga-
nocopper reagents, this chemistry has been recently
extended to the formation of C–N bonds with remarkable
efficiency. This resulted in noteworthy studies by
Yamamoto [14], Snieckus [15], Ricci [16, 17], and
Knochel [18–21], who demonstrated the full potential of
the oxidative coupling of amidocuprates and developed
especially efficient and mild amination procedures based
on this chemistry (Scheme 1, Eq. 3). The oxidation chem-
istry of trifluoromethyl/perfluoroalkyl organocopper has in
addition been extensively studied in the last couple of years,
as evidenced with the development of most efficient oxida-
tive trifluoromethylation/perfluoroalkylation of arylboronic
acids/boronates using stable, pre-formed trifluoromethyl/
perfluoroalkyl copper complexes (Scheme 1, Eq. 4) [22–24].
Although the oxidative cross-coupling of aryl, alkenyl-,
alkyl-, and perfluoroalkyl-copper/cuprate reagents have
therefore been extensively studied recently, copper acety-
lides 2 have for some reasons been left aside from those
studies, despite the high potential of their oxidation
chemistry for the development of mild alkynylation reac-
tions. Stimulated by the potential of strategies based on the
oxidation of alkynylcopper reagents and motivated by our
experience in copper-catalyzed alkynylation of heteronu-
cleophiles [25–30], we started investigating this area in
2011 and reported efficient processes for the aerobic
Keywords Organocopper reagents ꢀ Copper acetylides ꢀ
Oxidative coupling ꢀ Boronic acids ꢀ Alkynes ꢀ
Transmetallation
Introduction
Although organocopper reagents have found numerous
applications in organic synthesis such as in conjugate
0
additions, S 2/S 2 reactions, and carbocuprations, their
N
N
behavior in the presence of oxidants has long been a syn-
onym for serious side reactions leading to the formation of
undesired dimerization products, even though most useful
procedures based on this concept such as the Glaser-Hay
coupling [1–3] have been known for more than a century.
Despite remarkable systematic studies by Whitesides on
the oxidative dimerization of organocuprates and cross-
coupling from mixed cuprates in the 1960s and 1970s
F. Verna ꢀ C. Guissart ꢀ J. Pous ꢀ G. Evano (&)
Laboratoire de Chimie Organique, Service de Chimie et
PhysicoChimie Organiques, Universit e´ Libre de Bruxelles,
Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
e-mail: gevano@ulb.ac.be
123

5
24
F. Verna et al.
oxidant
R CuLi
R R
(eq. 1)
(eq. 2)
2
R = alkyl, aryl, alkenyl
oxidant
RR'CuLi
R R'
R, R' = alkyl, aryl
R'
HN
R"
R CuLi
2
R'
oxidant
R(NR'R")CuLi
R N (eq. 3)
R"
R'
RCu
Li
N
R"
R = alkyl, aryl, alkenyl
RO
RO
oxidant
CF CuLn
F3C Ar
(eq. 4)
3
B Ar
Scheme 1
Scheme 2
Scheme 3
alkynylation of N- and P- nucleophiles with copper acet-
ylides (Scheme 2) [31, 32]. Indeed, by simply stirring these
bench-stable polymeric reagents 2 (except for the copper
derivatives of acetylene and p-diethynylbenzene, alkynyl-
copper reagents are stable to shock and heat [33]), which
are readily prepared by reaction of the corresponding
alkynes 1 and cuprous iodide in a mixture of aqueous
ammonia and ethanol or in DMF in the presence of
potassium carbonate, with the desired heteronucleophiles
In this article, we report results based on this hypothesis,
which enabled the development of a facile oxidative cross-
coupling of copper acetylides with arylboronic acids
(
lactams and oxazolidinones 3, imines 5, or dial-
(for copper-catalyzed oxidative cross-coupling of terminal
kylphosphites 7) in the presence of simple activating
ligands under an atmosphere of oxygen, the corresponding
ynamides 4 [31], ynimines 6 [32], and alkynylphospho-
nates 8 [31] are smoothly obtained at room temperature
under especially mild and practical conditions.
alkynes with arylboronic acids, see [34–36]; for palladium-
catalyzed oxidative cross-coupling of terminal alkynes
with arylboronic acids, see [37–40]; for gold-catalyzed
oxidative cross-coupling of terminal alkynes with arylbo-
ronic acids, see [41]; for iron-catalyzed oxidative cross-
coupling of terminal alkynes with arylboronic acids, see
The success met during the development of these effi-
cient procedures based on the oxidative cross-coupling
with copper acetylides, which are thought to proceed by
oxidation of the alkynylcopper(I) and coordination of the
nucleophile to the electrophilic copper center followed by
reductive elimination, prompted us to further explore their
chemistry. We therefore decided to check if we could
replace the heteronucleophiles used in these processes by
organometallic reagents such as organoboron derivatives to
investigate whether an oxidation/transmetallation/reductive
elimination pathway would still be operative (Scheme 3).
[
42]; for palladium-catalyzed cross-coupling involving
electrogenerated silver acetylides, see [43]).
Results and discussion
Optimization of the oxidative cross-coupling
To test this hypothesis, we decided to investigate the cross-
coupling between (4-methoxyphenylethynyl)copper (11)
1
23

Expanding the oxidative chemistry of organocopper reagents
525
and 4-tolylboronic acid (12), the latter being used in excess
(
solvent or solvent mixtures in which the boronic acid was
fully soluble and with various polarities: THF, 1,4-dioxane,
CH Cl /DMF (90/10), toluene/DMF (95/5), acetonitrile/
two equivalents) to minimize the homocoupling of the
former. As in our oxidative cross-coupling with heteronu-
cleophiles, oxygen was chosen as the oxidant for practical
reasons (abundance, low cost, lack of toxic byproducts),
DMF as the solvent, and the efficiency of different
2
2
DMF (80/20), and DMF (Fig. 2). Among all the solvents/
solvent systems screened, 1,4-dioxane turned out to be by
far the best and allowed minimizing the amount of
homodimer 14 formed. While we could not completely
suppress the formation of the latter, the use of 1,4-dioxane
considerably reduced its formation, the optimized ratio
13:14 being 9:1 with this solvent, which allowed for the
isolation of the desired cross-coupled product 13 in 75 %
yield after column chromatography. Importantly, a control
experiment performed under nitrogen showed that no
coupling occurred at all, the starting copper acetylide being
unchanged in the absence of oxygen after 3 days at room
temperature.
0
additives (pyridine, TMEDA, 1,10-phenanthroline, 2-2 -
bipyridine, triphenylphosphine, N-methylimidazole, and
1
,2-dimethylimidazole) susceptible to trigger the reaction
at room temperature was evaluated (Fig. 1). Among all
these ligands, pyridine and triphenylphospine were found
to be totally inefficient and did not promote the reaction,
both starting materials being recovered after 3 days. Full
conversion was observed with all other ligands and in all
cases, mixtures of the desired aromatic alkyne 13 and diyne
byproduct 14 were obtained, the ratio being determined by
GC analysis of crude reaction mixtures. Among all ligands
evaluated, 1,10-phenanthroline was the most efficient, a
one-to-one mixture of 13 and 14 being formed with this
promoter.
Scope of the oxidative cross-coupling
Having the optimized conditions in hand, we next exam-
ined the scope and limitations of this procedure by looking
at the reactivity of a set of representative alkynylcopper
reagents and arylboronic acids (Fig. 3). As shown by these
results, aromatic-substituted copper acetylides performed
well in the oxidative cross-coupling and provided the
Further screening of the reaction conditions involved
examination of various solvents using 1,10-phenanthroline
as the ligand to evaluate the solvent effect on the ratio of
products resulting from cross-coupling and dimerization.
The influence of solvent was therefore next examined using
Fig. 1 Compared efficiency of
ligands for the alkynylation of
4
-tolylboronic acid. Standard
conditions: 0.25 mmol 11,
.5 mmol 12, 0.25 mmol
0
(
(
O
if bidentate) or 0.5 mmol
if monodentate) ligand, 1 atm
3
, 1 cm DMF, rt, 72 h
2
123

5
26
F. Verna et al.
Fig. 2 Compared efficiency of
solvents for the alkynylation of
4-tolylboronic acid. Standard
conditions: 0.25 mmol 11,
0
1
1
.5 mmol 12, 0.25 mmol 1,
0-phenanthroline, 1 atm O
2
,
3
cm solvent, rt, 72 h
corresponding aromatic alkynes in moderate to good yields
regardless of the electronic properties of the aromatic rings
that can be substituted with electron donating (e.g., 13
obtained in 75 % yield) or withdrawing (e.g., 15 obtained
in 58 % yield) substituents. In contrast, alkyl-substituted
alkynylcopper reagents such as undec-1-yn-1-ylcopper
were found to be poor reaction partners, only traces of the
corresponding cross-coupled product 20 being detected in
the reaction mixture. The electronic properties of the starting
arylboronic acids were also found to have a strong influence
on the outcome of the reaction, electron-rich boronic acids
being by far superior to electron-poor ones (compare for
example the yields of 17 and 19 with those of 21 and 22), the
competitive homodimerization of the starting copper acety-
lide being the major side reaction in the last case, which
might be attributed to a faster transmetallation in the case
of electron-donating substituents on the arylboronic acid.
Interestingly, the reaction is compatible with various sub-
stituents such as aromatic nitrile or aldehyde, and even the
presence of an additional ferrocene on the starting copper
acetylide did not interfere with the oxidative cross-coupling.
In all cases, the attractiveness of this procedure lies in its
simplicity since the desired aromatic alkynes are readily
obtained by simply stirring a combination of the starting
arylboronic acid, the alkynylcopper reagent, and phenan-
throline in reagent-grade 1,4-dioxane under oxygen at
room temperature. From a practical point of view, it ought
to be mentioned that the endpoint of the reaction is
remarkably easy to detect since the reaction mixture turns
from a heterogeneous yellow suspension to a brownish
homogeneous solution upon completion, which can then be
concentrated and directly loaded onto silica gel to elimi-
nate the excess of boronic acid and the copper(II)
complexes formed in the process.
Oxidative cross-coupling in 2,6-lutidine media
To further expand the scope of this oxidative cross-cou-
pling, we next looked at the reactivity of heteroarylboronic
acids and chose 3-quinolinylboronic acid (25) as a test
substrate. Using our standard conditions for the cross-
coupling with phenylethynylcopper (24), the corresponding
3-(phenylethynyl)quinoline (26) was however obtained in
11 % yield only (conditions A), dimerization of both the
starting copper acetylide and boronic acid being serious
side reactions in this case (Scheme 4). Capitalizing on the
1
23

Expanding the oxidative chemistry of organocopper reagents
527
Fig. 3 Scope of the oxidative cross-coupling of copper acetylides and arylboronic acids (bonds formed shown in bold)
Scheme 4
remarkable selectivity obtained by the Kobayashi group for
the aerobic copper-catalyzed oxidative cross-coupling of
alkynes with arylboronic acids in 2,6-lutidine at 45 °C
The efficiency of this alternative modified procedure
was briefly evaluated with a couple of substrates (Fig. 4),
and if the yields could be improved in some cases, this
improvement was not systematic, and this other system was
therefore complimentary to the first one.
[
36], we evaluated the use of this co-solvent in combina-
tion with methanol and were delighted to note that the
dimerization could be reduced, the desired substituted
quinoline 26 being obtained in 50 % yield provided that the
phenanthroline was added portion-wise to further slow
down the competitive dimerization processes (conditions
B). Interestingly, 1,10-phenanthroline is still required with
this solvent system, 2,6-lutidine alone being inefficient to
promote the oxidative cross-coupling.
Conclusion
In conclusion, we have developed an efficient procedure
for the oxidative cross-coupling between arylboronic acids
and alkynylcopper reagents. Upon simple addition of 1,10-
123

5
28
F. Verna et al.
Fig. 4 Oxidative cross-
coupling of copper acetylides
and arylboronic acids in 2,6-
lutidine/methanol (bonds
formed shown in bold, yield
obtained in 1,4-dioxane
indicated in parentheses for
comparison)
1 13
Table 1 Product yields and references reporting H/ C NMR
spectra
refer to chromatographically and spectroscopically pure
compounds.
Product
Yield/%
conditions A)
Yield/%
(conditions B)
References
(
General procedure (conditions A for reactions
in 1,4 dioxane)
1
1
1
1
1
1
2
2
2
2
3
5
6
7
8
9
1
2
3
6
75
58
31
66
67
71
42
58
33
11
–
[44]
[45]
[45]
[44]
[45]
[46]
[47]
[35]
[48]
[49]
–
3
A 5-cm round bottom flask was successively charged with
59
72
–
the boronic acid (1.0 mmol), 90 mg 1,10-phenanthroline
3
0.5 mmol), and 2 cm 1,4-dioxane. When the starting
(
boronic acid was not fully dissolved, additional N,N-
dimethylformamide was slowly added until complete dis-
3
solution (typically 0.5–1.5 cm ). The alkynylcopper reagent
72
5
–
(0.5 mmol) was next added to the reaction mixture, which
–
was then vigorously stirred at room temperature and under
atmosphere of oxygen (balloon) until complete disappear-
ance of the alkynylcopper reagent (complete dissolution to a
brownish homogeneous solution; typically 48–72 h). When
the reaction was run in 1,4-dioxane only, the crude reaction
mixture was filtered over a plug of silica gel (washed with
EtOAc) and concentrated. When additional DMF was
required, the reaction was diluted with an aqueous mixture
of saturated ammonium chloride and 28 % ammonium
hydroxide (1:1 solution) and extracted with ethyl acetate.
Combined organic layers were washed with brine, dried over
50
phenanthroline in the presence of oxygen, these highly
stable, readily available polymeric reagents are readily
activated and transfer their alkynyl group after subsequent
transmetallation with the boronic acid. These results further
expand the oxidative chemistry of organocopper com-
pounds together with providing a user-friendly entry to
diaryl acetylenes.
MgSO , and concentrated. The crude residue was in both
4
cases purified by flash chromatography over silica gel to
give the desired aromatic alkynes (see Table 1 for yields and
Experimental
1 13
references reporting H/ C NMR spectra).
0
0
All solvents were reagent grade. Pyridine, N,N,N ,N -tet-
ramethylethylenediamine, and 2,6-lutidine were distilled
from calcium hydride. Copper acetylides were prepared
from the corresponding alkynes using our previously
reported procedures [31]. All other reagents were used
as supplied. Reactions were magnetically stirred. Yields
General procedure (conditions B for reactions
in 2,6-lutidine/methanol)
3
In a 5-cm round bottom flask, the boronic acid (1.0 mmol)
3
was dissolved in 1 cm methanol and 1 cm 2,6-lutidine.
3
1
23

Expanding the oxidative chemistry of organocopper reagents
529
17. Cane F, Brancaleoni D, Dembech P, Ricci A, Seconi G (1997)
`
Synthesis p 545
The alkynylcopper reagent (0.5 mmol) was next added to
the reaction mixture, which was then vigorously stirred at
room temperature and under atmosphere of oxygen (bal-
loon). 1,10-Phenanthroline was next added portion-wise
1
8. del Amo V, Dubbaka SR, Krasovskiy A, Knochel P (2006) An-
gew Chem Int Ed 45:7838
19. Boudet N, Dubbaka SR, Knochel P (2008) Org Lett 10:1715
20. Kienle M, Dubbaka SR, del Amo V, Knochel P (2007) Synthesis
p 1272
(
5 9 9 mg, 5 9 0.05 mmol) every 2 h, and the reaction
mixture was kept under vigorous stirring at room temper-
ature and under atmosphere of oxygen until complete
disappearance of the alkynylcopper reagent (complete
dissolution to a brownish homogeneous solution; typically
2
2
1. Kienle M, Dunst C, Knochel P (2009) Org Lett 11:5158
2. Litvinas ND, Fier PS, Hartwig JF (2012) Angew Chem Int Ed
51:536
23. Nova
Ed 51:7767
4. Zanardi A, Nokinov MA, Martin E, Benet-Buchholz J, Grushin
VV (2012) J Am Chem Soc 133:20901
´
k P, Lishchynskyi A, Grushin VV (2012) Angew Chem Int
4
8–72 h). The crude reaction mixture was next filtered over
2
a plug of silica gel (washed with EtOAc) and concentrated.
The crude residue was then purified by flash chromatog-
raphy over silica gel to give the desired aromatic alkynes
25. Coste A, Karthikeyan G, Couty F, Evano G (2009) Angew Chem
Int Ed 48:4381
26. Jouvin K, Couty F, Evano G (2010) Org Lett 12:3272
1
13
(
see Table 1 for yields and references reporting H/ C
2
2
7. Jouvin K, Evano G (2011) Chim Oggi 29:31
8. Laouiti A, Rammah MM, Rammah MB, Marrot J, Couty F,
Evano G (2012) Org Lett 14:6
NMR spectra).
Acknowledgments We are grateful to the Universit e´ Libre de
Bruxelles (ULB) for financial support. GE is indebted to Prof. Ivan
Jabin for his most generous help during his installation at the ULB.
29. Jouvin K, Bayle A, Legrand F, Evano G (2012) Org Lett 14:1652
30. Jouvin K, Coste A, Bayle A, Legrand F, Karthikeyan G, Tadi-
parthi K, Evano G (2012) Organometallics 31:7933
3
3
1. Jouvin K, Heimburger J, Evano G (2012) Chem Sci 3:756
2. Laouiti A, Jouvin K, Rammah MM, Rammah MB, Evano G
(
2012) Synthesis 44:1491
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