Copper-catalyzed synthesis of alkynylphosphine derivatives: Unprecedented use of nucleophilic phosphorus compounds

Article abstract of DOI:10.1039/c0cc04645k

A new and smooth approach towards alkynylphosphine derivatives is described. It relies on the unprecedented catalytic coupling of secondary phosphine boranes with alkynyl bromides using the CuI/1,10-phenanthroline couple.

Full text of DOI:10.1039/c0cc04645k

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COMMUNICATION
Copper-catalyzed synthesis of alkynylphosphine derivatives:
unprecedented use of nucleophilic phosphorus compoundsw
Elise Bernoud, Carole Alayrac, Olivier Delacroix and Annie-Claude Gaumont*
Received 27th October 2010, Accepted 10th January 2011
DOI: 10.1039/c0cc04645k
A
new and smooth approach towards alkynylphosphine
derivatives is described. It relies on the unprecedented catalytic
coupling of secondary phosphine boranes with alkynyl bromides
using the CuI/1,10-phenanthroline couple.
Phosphines play a key-role as ligands in transition metal
catalysis, and as chiral controllers in asymmetric processes.1
The design of new phosphine structures, which allow the
tuning of the steric and electronic properties of the organo-
metallic complexes employed as catalysts, is essential for the
expansion of the scope of available catalytic transformations.
For this purpose alkynylphosphines2 are attractive building
blocks in view of the rich and diverse chemistry of the alkynyl
function.3 Moreover they also deserve interest as useful
ligands for homogeneous catalysis because of their unique
structural feature due to the linearity of the triple bond.4,5
The few known methods for the preparation of alkynyl-
phosphines involve the nucleophilic substitution reaction at
the phosphorus atom of a halophosphine by a metal acetylide
at low temperature.6 A catalytic variant, recently developed,
consists in the cross-coupling reaction of terminal alkynes with
chlorophosphines catalyzed by nickel, palladium or copper
complexes.7 The application of these methods to the
asymmetric series5 is tricky, because of the limited access to
unsymmetrical halophosphines and their weak configurational
stability. Thus, the emergence of complementary phosphination
reactions should expand the range of available racemic and
P-stereogenic derivatives. The obvious alternative, the direct
C–P bond formation via oxidative coupling with terminal
alkynes, as recently described for the synthesis of alkynyl-
phosphonates,8 is difficult to envisage due to the highly
oxidizable nature of phosphine derivatives. As part of our
research program dedicated to the development of new catalytic
syntheses of phosphines,9 we report here the unprecedented
use of nucleophilic phosphorus compounds for the preparation
of alkynylphosphines through Cu(I)-catalyzed cross-coupling
Scheme 1 Strategies for the synthesis of alkynylphosphines.
reaction between secondary phosphine boranes and 1-bromo-
alkynes (Scheme 1).
In the context of the fast expanding area of copper-
catalyzed carbon–heteroatom cross-coupling reactions,10 the
phosphorus series has been neglected.8,11,12 Only 3 publications
report the use of phosphines as cross-coupling partners,11
presumably because of the high affinity of phosphines to
bound coinage metals. In order to limit the possible poisoning
of the copper catalyst, we selected phosphine boranes13 as
phosphinating agents and the readily available 1-bromoalkynes,14
recently used with success as coupling partners in the catalytic
synthesis of N-functionalized alkynes.
To initiate our study we examined the reaction between
diphenylphosphine borane 1a and 1-bromohexyne 2a. A
preliminary screening of the conditions allowed us to select
CuI (10 mol%) as the copper source, K2CO3 (2 equiv.) as the
base, toluene as the solvent and a mild temperature of 40 1C.
Under these conditions, 35% of the expected product was
formed. Worthy of note is that copper is required to promote
the coupling, no reaction occurring when it is omitted (Table 1,
entry 1 vs. 2).
To improve the conversion, a bidentate ligand was combined
with copper. The known ability of amines to favour the
decomplexation13,15 of phosphine boranes led us to select
1,10-phenanthroline,16 a less basic ligand. Screening of various
catalyst loadings and ligand/copper ratios showed that
the most appropriate catalytic conditions consisted of
Cu(I)I/phenanthroline in a 1 : 1 ratio (10 mol%). Once the
suitable catalytic system was established, various solvents and
bases were screened. Toluene proved to be optimal whereas
highly coordinating polar solvents such as acetonitrile or THF
prevented the reaction to occur. Among the most common
bases employed for copper catalysis, K2CO3 afforded the best
´
Laboratoire de Chimie Moleculaire et Thio-organique,
UMR CNRS 6507, INC3M, FR 3038, ENSICAEN & Universite´ de
´
Caen, 6 boulevard du Marechal Juin, 14050 Caen, France.
E-mail: annie-claude.gaumont@ensicaen.fr; Fax: +33 231 45 28 77;
Tel: +33 231 45 28 73
w Electronic supplementary information (ESI) available: Experimental
details, characterization data and NMR spectra of new compounds.
See DOI: 10.1039/c0cc04645k
c
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Chem. Commun., 2011, 47, 3239–3241 3239

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Table 1 Optimisation of the coupling reaction between 1a and 2aa
Table 2 Scope of the copper-catalyzed cross-coupling reaction of
secondary phosphine boranes with alkynyl bromidesa
Catalytic
Entry system
Base
(equiv.)
Conv.
T/1C Time/h (%)
3ab (%)
Entry 2 (R)
2a (n-Bu)
Alkynylphosphine
3
Time/h Yieldb (%)
1
2
3
4
5
6
7
CuI
—
K2CO3 (2) 40
K2CO3 (2) 40
16
16
3.5
3.5
3.5
5
61
0
100
91
99
46
100
35
0
100
81
86
46
100
CuI/L 1 : 1 K2CO3 (2) 40
CuI/L 1 : 1 Cs2CO3 (2) 40
CuI/L 1 : 1 K3PO4 (2) 40
CuI/L 1 : 1 K2CO3 (1) 40
CuI/L 1 : 1 K2CO3 (2) 20
1
2
3
4
5
6
7
8
9
3a
5
74c
69c
55
69
59
60
58
58
59
2b (C10H21
2c (TIPS)
2d (Ph)
)
3b 16
3c 16
5.5
a
Reaction conditions: 1a (50 mg, 0.25 mmol), 2a (1 equiv.), CuI
(10 mol%), L = 1,10-phenanthroline (10 mol%), base (1 or 2 equiv.),
toluene (4 mL). Measured from the crude product by 31P NMR.
b
3d
5
results (Table 1, entry 3 vs. 4 or 5). Under optimized conditions,
the complete conversion of 1a into 3a was reached after only
3.5 h at 40 1C (entry 3).17 Interestingly, a 1 mol% catalyst
loading was also suitable to reach full conversion providing
that the reaction time was extended to 38 h. Reducing the
amount of base from 2 to 1 equiv. had a detrimental effect on
the conversion (entry 6), probably because of the weak
solubility of K2CO3 in toluene. It is worth noting that with
the CuI/phenanthroline couple, the reaction proceeded even at
room temperature leading to a full conversion after only 5.5 h
(entry 7). The purification was performed by silica gel flash
chromatography, affording phosphine borane 3a in 74% yield
(Table 2, entry 1). Importantly, the reaction was scaled-up to
gram-scale with similar yields.
2e (o-MeO–Ph)
3e 20
3f 38
3g 38
3h 38
3i 38
2a
2b
2c
2d
10
2a
2d
3j 21
3k 20
50d
52d
11
The scope and limitations of this reaction were then evaluated
by testing a range of alkynyl bromides as coupling partners
with diphenylphosphine borane 1a (Table 2). Like 2a, alkyl
bromoalkyne 2b readily underwent the cross coupling reaction
at 40 1C (entry 2), whereas a temperature of 60 1C was more
suitable for the bulky silylated 1-bromoalkyne 2c (entry 3) and
for aryl 1-bromoalkynes 2d–e (entries 4 and 5). By contrast
electron-deficient 1-bromoalkynes (R = CO2Me, 4-NO2Ph)
failed to react under the defined conditions.
a
Reaction conditions: 1a–c (0.75 or 0.96 mmol), 2a–e (1 equiv.), CuI
(10 mol%), 1,10-phenanthroline (10 mol%), K2CO3 (2 equiv.), toluene
b
c
(12 or 16 mL), 60 1C. Isolated yields. Reaction was run at
40 1C. K3PO4 (2 equiv.) was used.
d
iodides with diphenylphosphine.11 To account for this result,
we propose that both the use of an activated phosphine
(phosphine borane complex) and of an alkyne derivative,
which might be functioning as a p-Lewis base to copper,
favour the process.18
We next examined the scope of secondary phosphine boranes.
It is important to recall that, due to its higher reactivity
compared to phosphines bearing alkyl substituents, diphenyl-
phosphine is often the only phosphine used in coupling
reactions. This is a strong limitation in term of diversity.
Interestingly, under the conditions previously defined, diethyl-
phosphine borane 1b, selected as a model of alkylphosphines,
was cleanly converted into the coupling products 3f–i
(full conversion after 38 hours, Table 2, entries 6–9). In the
case of methylphenylphosphine borane 1c, K3PO4 was preferred
to ensure a complete conversion (20 h at 60 1C). The corres-
ponding alkynylphosphines 3j–k were isolated in 50–52%
yields (entries 10 and 11). This result is of interest since it
opens the way to the development of an enantioselective
version of the reaction through the use of a chiral ligand
associated to a copper(I) salt. The mild conditions used (20 to
60 1C) strongly contrast with the harsh conditions (110 1C,
15 h) required for the copper-catalyzed cross-coupling of aryl
Despite the recent progress achieved in copper-catalyzed
coupling reactions regarding the scope and the smoothing of
the reaction conditions, the mechanistic fundamentals are still
poorly documented in the literature. According to some recent
theoretical and experimental studies,19 ligand-bound copper(I)-
nucleophiles are the reactive intermediates involved in the
catalytic arylation of N- and O-nucleophiles. In our case, a
working hypothesis could involve the initial formation of a
copper(I) phosphide species as nucleophile. Since the phosphorus
atom in phosphine borane is tetrahedral, its deprotonation has
to take place prior to the complexation to copper. In order to
validate this hypothesis, we performed the reaction under
stoichiometric conditions. Deprotonation of 1a was achieved
with n-BuLi (1 equiv.) and the resulting lithiated anion
(dP = À31 ppm) was first treated with CuI (1 equiv.) at 0 1C
c
3240 Chem. Commun., 2011, 47, 3239–3241
This journal is The Royal Society of Chemistry 2011

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Scheme
2 Tentative mechanistic cycle for the copper-catalyzed
synthesis of alkynylphosphine derivatives.
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then with 1,10-phenanthroline (1 equiv.). The 31P NMR
spectrum revealed the instant formation of a new phosphorus
derivative (dP = À22 ppm), which was attributed to the
copper phosphide species [Ph2P(BH3)Cuphen] based on the
1H and 13C NMR spectra. All attempts to grow crystals from
this complex failed. 1-Bromoalkyne 2a (1.4 equiv.) was
added to this complex at 0 1C and the reaction medium was
subsequently heated at 40 1C. A 31P NMR spectrum registered
after 2 h of heating showed the expected signal corresponding
to alkynylphosphine 3a (dP = 5 ppm). Based on this result,
and by analogy to related catalytic syntheses of N-functionalized
alkynes,20 a tentative mechanism is shown in Scheme 2: (i)
formation of Cu(I) phosphide species 4, (ii) oxidative addition
to 1-bromoalkyne 2, (iii) reductive elimination leading to
cross-coupling product 3 and regeneration of the copper
catalyst.
In conclusion we have developed a new and efficient access
to various alkynylphosphine derivatives, through copper-
catalyzed cross-coupling reaction between alkyl, aryl and
alkylaryl phosphine boranes and various 1-bromoalkynes.
Worthy of note are the mild conditions (20 to 60 1C) required
in this coupling reaction, and the first use of a nucleophilic
phosphorus derivative in the catalytic synthesis of alkynyl-
phosphines. Preliminary mechanistical studies are consistent with
the involvement of a copper phosphide as an intermediate. The
reaction mechanism and the extension of this methodology to the
asymmetric series are currently under investigation.
This work was supported by CNRS and Crunch
´
gion
(interregional organic chemistry network). The )Re
Basse-Normandie* and ERDF funding (ISCE-Chem
&
INTERREG IVa program) are gratefully thanked for financial
support. COST ACTION CM0802 ‘‘PHOSCINET’’ is also
acknowledged for support.
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Notes and references
17 Other copper sources such as CuBr, Cu2O, CuBr2 in combination
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This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3239–3241 3241