Unprecedented synthesis of alkynylphosphine-boranes through room-temperature oxidative alkynylation

Article abstract of DOI:10.1021/ol402197d

An original and user-friendly synthesis of alkynylphosphine-boranes, useful building blocks in organic synthesis, based on an oxidative P-alkynylation reaction with readily available copper acetylides is reported. The ability of a secondary phosphine protected with a borane to undergo oxidative coupling without oxidation of the P-moiety is demonstrated for the first time. The reaction, which proceeds at room temperature, is applicable to the preparation of enantioenriched and structurally complex alkynylphosphine-boranes.

Full text of DOI:10.1021/ol402197d

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Unprecedented Synthesis of
Alkynylphosphine-boranes through
Room-Temperature Oxidative Alkynylation
†
‡
§
,‡
ꢀ
ꢀ
Kevin Jouvin, Romain Veillard, Cedric Theunissen, Carole Alayrac,*
Annie-Claude Gaumont,*,‡ and Gwilherm Evano*,§
ꢀ
Institut Lavoisier de Versailles, UMR CNRS 8180, Universite de Versailles Saint-Quentin
en Yvelines, 45, avenue des Etats-Unis, 78035 Versailles Cedex, France, Laboratoire de
ꢀ
Chimie Moleculaire et Thioorganique, UMR CNRS 6507, INC3M, FR3038, ENSICAEN
ꢀ
& Universite de Caen Basse-Normandie, 6 bvd Marechal Juin, 14050 Caen, France, and
Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques,
ꢀ
ꢀ
Universite Libre de Bruxelles, Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
carole.witulski-alayrac@ensicaen.fr; annie-claude.gaumont@ensicaen.fr; gevano@ulb.ac.be
Received August 2, 2013
ABSTRACT
An original and user-friendly synthesis of alkynylphosphine-boranes, useful building blocks in organic synthesis, based on an oxidative
P-alkynylation reaction with readily available copper acetylides is reported. The ability of a secondary phosphine protected with a borane to
undergo oxidative coupling without oxidation of the P-moiety is demonstrated for the first time. The reaction, which proceeds at room
temperature, is applicable to the preparation of enantioenriched and structurally complex alkynylphosphine-boranes.
Heterosubstituted alkynes are among the most useful
and versatile building blocks in organic synthesis with
applications in medicinal chemistry or material science.1ꢀ3
The rich and diverse chemistry of the alkynyl function
allows for the introduction of a broad array of functional-
itiesinto organicmolecules. Taking advantage ofthe strong
polarization of the triple bond resulting from the presence
of the heteroatom, heterosubstituted alkynes have been
extensively used for the design of remarkably efficient and
highly regio- and stereoselective transformations. In addi-
tion, the development of intramolecular reactions from
these heterosubstituted alkynes enabled the emergence of
new paradigms in heterocyclic chemistry.
While nitrogen-substituted alkynes (ynamines and
ynamides)1 and oxygen/sulfur-substituted acetylenes
(alkynyl(thio)ethers)2 have been extensively studied during
the past decade, the chemistry of their phosphorus
analogues, and especially alkynylphosphines and alkynyl-
phosphine-boranes, have been far less investigated.3 They
however represent a class of heterosubstituted alkynes
which holds great potential for the development of
metal-catalyzed reactions, as demonstrated recently by
the groups of Imamoto and Sawamura who used them as
efficient ligands in asymmetric rhodium-catalyzed hydro-
genation and conjugated addition reactions,4 asymmetric
palladium-catalyzed alkylative ring-opening reactions,4
and gold-catalyzed cyclization of acetylenic β-ketoesters
†
ꢀ
Universite de Versailles Saint-Quentin en Yvelines.
‡
§
ꢀ
ENSICAEN & Universite de Caen Basse-Normandie.
ꢀ
Universite Libre de Bruxelles.
(1) (a) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010,
49, 2840. (b) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.;
Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064. (c) Evano, G.;
Jouvin, K.; Coste, A. Synthesis 2013, 45, 17.
(2) (a) Witulski, B.; Alayrac, C. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations; de Meijere, A., Ed.; Thieme:
Stuttgart, 2005; Vol. 24, pp 933ꢀ956. (b) Potapov, V. A.; Trofimov,
B. A. In Science of Synthesis: Houben-Weyl Methods of Molecular
Transformations; de Meijere, A., Ed.; Thieme: Stuttgart, 2005; Vol. 24,
pp 957ꢀ1005.
ꢀ
(3) (a) Pietrusiewicz, K. M.; Stankevic, M. In Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations; de Meijere, A.,
Ed.; Thieme: Stuttgart, 2005; Vol. 24, pp 1073ꢀ1086. (b) Kondoh, A.;
Yorimitsu, H.; Oshima, K. Chem.;Asian J. 2010, 5, 398. (c) Bernoud,
E.; Veillard, R.; Alayrac, C.; Gaumont, A.-C. Molecules 2012, 17, 14573.
(4) Imamoto, T.; Saitoh, Y.; Koide, A.; Ogura, T.; Yoshida, K.
Angew. Chem., Int. Ed. 2007, 46, 8636.
r
10.1021/ol402197d
XXXX American Chemical Society

or acetylenic silyl enol ethers.5 Alkynylphosphine-boranes
have also been used as substrates in regio- and stereoselec-
tive carbocuprations and hydroaluminations, reactions that
further demonstrated their potential in organic synthesis.6b
As for most classes of heterosubstituted alkynes, difficul-
ties associated with their synthesis have considerably ham-
pered their full development. Most existing routes suffer
from limitations in terms of yields, scope, and reaction
conditions when they do not rely on the use of toxic or
nonpractical reagents. Indeed, alkynylphosphine-boranes 3,
stable precursors of alkynylphosphines, are typically pre-
pared by the reaction between bromophosphine-boranes 2
and lithium acetylides 14 or by borane complexation of
alkynylphosphines, in situ generated from chlorophosphines
5 and acetylenic Grignard reagents 4 (Scheme 1).6 More
recently, 3 have been shown to be conveniently prepared by
a copper-catalyzed direct alkynylation of secondary phos-
phine-boranes 7 with bromoalkynes 6.7 Catalytic protocols
based on the use of terminal alkynes and nickel or copper
complexes were also proposed recently for the synthesis of
alkynylphosphines8a,b and alkynylphosphonates.8c
for the alkynylation of heteronucleophiles under mild con-
ditions,10 we envisioned that alkynylphosphine-boranes 3
could be obtained by reacting secondary phosphine-
boranes 7 with stable, readily available copper acetylides
8 in the presence of a chelating ligand and an oxidant
(Scheme 1).11 The well-known high sensitivity of phos-
phines toward oxidation motivated our choice of using
their borane complexes.12 Provided that the oxidative
transfer of the alkynyl group from copper to phosphorus
from alkynylcopper 8 is faster than their dimerization
and the oxidation of 7, this would offer a useful and
user-friendly entry to alkynylphosphine-boranes 3 under
mild conditions.
To test this challenging hypothesis, dicyclohexyl-
phosphine-borane 7a and octynylcopper 8a were chosen
as model substrates for the optimization step. Among all
possible oxidants, oxygen was chosen for obvious practical
reasons, and to minimize the dimerization of 8a, 2 equiv of
7a were used. Toluene was selected as the solvent in order
to avoid a possible competitive decomplexation of both
phosphine-boranes 7a and 3a, known to occur with co-
ordinating and/or basic solvents.7a For the same reason,
strongly chelating and basic ligands such as diamines were
discarded from this study and the efficiency of an excess of
various imidazole- or pyridine-type mono- or bidendate
conjugated N-ligands to promote the alkynylation at room
temperature without any additional base was evaluated
(Figure 1).13
Scheme 1. Previously Reported Syntheses of Alkynylphosphine-
boranes and Strategy Based on Copper Acetylides
While 2,20-bipyridine was surprisingly inefficient to
activate the copper acetylide in the presence of oxygen,
all other N-ligands were found to be suitable promoters,
with various efficiencies however. Indeed, while the use of
pyridine and 1-methyl-imidazole resulted in the formation
of the desired alkynylphosphine-borane 3a as the major
product, neither the homodimerization of the starting
copper acetylide 8a leading to 10 nor the deborylation/
oxidation yielding considerable amounts of alkynylpho-
sphine oxide 9 could be suppressed. The former could be
avoided with the more electron-rich 1,2-dimethylimidazole,
but the use of this ligand still resulted in 22% of 9.
Gratifyingly, switching to 1,10-phenanthroline resulted in
the clean formation of alkynylphosphine-borane 3a, which
could be isolated in 75% yield, together with traces of diyne
10(2%) and phosphine oxide 9 (5%). In aneffort to further
optimize the reaction conditions, we next evaluated the
In continuation of our studies on the development of
new syntheses of heterosubstituted alkynes7,9 and on the
use of readily available and bench-stable copper acetylides
(5) (a) Ochida, A.; Ito, H.; Sawamura, M. J. Am. Chem. Soc. 2006,
106, 16486. (b) Ito, H.; Ohmiya, H.; Sawamura, M. Org. Lett. 2010, 12,
4380.
(6) (a) Charrier, C.; Chodkiewicz, W.; Cadiot, P. Bull. Soc. Chim. Fr.
1966, 1002. (b) Ortial, S.; Montchamp, J.-L. Org. Lett. 2011, 13, 3134.
(7) (a) Bernoud, E.; Alayrac, C.; Delacroix, O.; Gaumont, A.-C.
Chem. Commun. 2011, 47, 3239. (b) Abdellah, I.; Bernoud, E.; Lohier,
J.-F.; Alayrac, C.; Gaumont, A.-C.; Toupet, L.; Lepetit, C. Chem.
Commun. 2012, 48, 4088.
(8) (a) Beletskaya, I. P.; Afanasiev, V. V.; Kazankova, M. A.;
Efimova, I. V. Org. Lett. 2003, 5, 4309. (b) Afanasiev, V. V.; Beletskaya,
I. P.; Kazankova, M. A.; Efimova, I. V.; Antipin, M. U. Synthesis 2003,
2835. (c) Gao, Y.; Wang, G.; Chen, L.; Xu, P.; Zhao, Y.; Zhou, Y.; Han,
L.-B. J. Am. Chem. Soc. 2009, 131, 7956.
(9) (a) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew.
Chem., Int. Ed. 2009, 48, 4381. (b) Jouvin, K.; Couty, F.; Evano, G. Org.
Lett. 2010, 12, 3272. (c) Laouiti, A.; Rammah, M. M.; Rammah, M. B.;
Marrot, J.; Couty, F.; Evano, G. Org. Lett. 2012, 14, 6. (d) Jouvin, K.;
Bayle, A.; Legrand, F.; Evano, G. Org. Lett. 2012, 14, 1652. (e) Jouvin,
K.; Coste, A.; Bayle, A.; Legrand, F.; Karthikeyan, G.; Tadiparthi, K.;
Evano, G. Organometallics 2012, 31, 7933.
(10) (a) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3,
756. (b) Laouiti, A.; Jouvin, K.; Rammah, M. M.; Rammah, M. B.;
Evano, G. Synthesis 2012, 44, 1491.
(11) Aves, S. J.; Spring, D. R. In Patai Series: The Chemistry of
Functional Groups. The Chemistry of Organocopper Compounds;
Rappoport, Z., Marek, I., Eds.; John Wiley & Sons Ltd.: Chichester, 2009;
Vol. 24, pp 585ꢀ602.
(12) (a) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato,
K. J. Am. Chem. Soc. 1990, 112, 5244. (b) Gaumont, A.-C.; Carboni, B.
In Science of Synthesis: Houben-Weyl Methods of Molecular Transfor-
mations; Kaufmann, D. E., Matteson, D. S., Eds.; Thieme: Stuttgart, 2005;
Vol. 6, pp 485ꢀ512.
(13) Preliminary experiments using 2 equiv of monodentate N-
ligands or 1 equiv of bidentate N,N-ligands resulted in clean reactions
but low yields, presumably due to in situ borane decomplexation and
coordination of the resulting alkynylphosphine to copper(II) salts.
Excess ligand would allow trapping the copper salts and avoid
decomplexation.
B
Org. Lett., Vol. XX, No. XX, XXXX

Figure 1. Compared efficiency of N-ligands for the alkynylation of
dicyclohexylphosphine-borane. Standard conditions: 0.12 mmol
of 8a, 0.24 mmol of 7a, 0.6 mmol (if bidentate) or 1.2 mmol
(if monodentate) of ligand, 1 atm of O2, 0.3 mL of toluene, rt, 8 h.
possibility of decreasing the amount of phosphine-borane.
By using 1.5 equiv instead of 2, the isolated yield of 3a (70%)
was minimally affected: thus a 1:1.5 ratio between reagents
8 and 7 was kept for the scope and limitation studies.
Figure 2. Oxidative alkynylation of dicyclohexylphosphine-bor-
ane with representative copper acetylides.
With the optimized conditions in hand, we next moved
to evaluate the scope of this reaction. Toward this goal, a
variety of copper acetylides 810a were reacted with dicyclo-
hexylphosphine-borane 7a using these optimized reaction
conditions (Figure 2). A variety of dicyclohexyl(alkynyl)-
phosphine-boranes 3aꢀs could be obtained by simply
treating a solution of dicyclohexylphosphine-borane 7a
with the appropriate copper acetylide 8 in the presence of
an excess of 1,10-phenanthroline (5 equiv) under an atmo-
sphere of oxygen at rt for 8 h. The corresponding alkynyl-
phosphine-boranes 3 were obtained in fair-to-good yields,
regardless of the nature of the substituent of the starting
copper acetylide 8. Indeed, alkyl- (3a-f), carboxy- (3h),
vinyl- (3i), or aryl- (3jꢀs) substituted alkynylphosphine
derivatives could be obtained with similar efficiencies,
except when starting from a copper acetylide containing
an unprotected alcohol which failed to give the correspond-
ing alkynylated product 3g. In the case of aryl-substituted
copper acetylides, the nature and position of the substituents
had little effect on the outcome of the reaction. Compared
to the alkynylation with bromoalkynes, it ought to be
mentioned that this procedure is especially convenient, from
a practical point of view, for the synthesis of alkynylpho-
sphine-boranes substituted with small chains (such as 3c, 3d,
or 3i), the bromoalkynes that would be required for their
synthesis, being highly volatile and strongly lachrymator.
The reaction scope was also investigated with respect to
the phosphorus-nucleophile using octynylcopper 8a and
various phosphine-boranes 7 (Figure 3). While the nature
of the copper acetylide was found to have little influence
on the outcome of the reaction, a marked difference
in reactivity was observed with the various phosphine-
boranes evaluated. Steric hindrance strongly affected the
reaction, with bulky substituents on 7 favoring the dimer-
ization of octynylcopper 8a. While an isopropyl group
was tolerated on the starting phosphine borane, with the
resulting alkynylphosphine-borane 3u being obtained in
70% yield, the presence of one (3w) or two (3x) tert-butyl
Figure 3. Oxidative alkynylation of representative phosphine-
boranes with octynylcopper.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Oxidative Alkynylation of Phosphine-boranes with
More Complex Substrates
Scheme 3. Gram-Scale Synthesis of Alkynylphosphine-boranes
and Postfunctionalization
the oxidative cross-coupling reactions described above, as
it could be conveniently performed from 1 g of commer-
cially available phenylethynylcopper 17, yielding the cor-
responding alkynylphosphine-borane 21 in 68% yield.
Further decomplexation with DABCO15a in THF under
argon then smoothly gave alkynylphosphine 22, a compound
that cannot be efficiently obtained by a direct alkynylation
of diethylphosphine which mostly gave pyrophosphate
Et2P(O)ꢀOꢀP(O)Et2. In addition, decomplexation and sub-
sequent treatment with tert-butylhydroperoxide15b directly
converted 21 into alkynylphosphine oxide 23.
In conclusion, we have developed an efficient and
practical synthesis of alkynylphosphine-boranes, useful
building blocks that can be obtained in a simple manner
by reaction with readily available copper acetylides in the
presence of 1,10-phenanthroline and oxygen at room
temperature. The successful use of secondary dialkylpho-
sphine-boranes as coupling partners under oxidative con-
ditions is unprecedented and solves the problem of
using highly oxidable secondary phosphines. This should
contribute to further extension of the synthetic utility of
alkynylphosphine derivatives in organic synthesis and ex-
pand the oxidative chemistry of organocopper compounds.
Application of this oxidative alkynylation to other nucleo-
philes is under study and will be reported in due time.
groups had a detrimental effect on the reaction. The bulky
alkynylated phosphine-boranes were however formed,
although in modest yields, which is quite remarkable since
di-tert-butylphosphine derivatives are typically poor part-
ners in cross-coupling reactions.14 The electronic property
of phosphine-borane 7 was found to be a crucial para-
meter, with the presence of one (3y) or two (3z) aryl groups
completely inhibiting the alkynylation.
Compared to other syntheses, a major advantage of our
procedure lies in the mildness of the reaction conditions
which do not require the use of strongly nucleophilic and
basic reagents such as lithium acetylides or heating. There-
fore, and to further test our procedure and demonstrate its
synthetic utility, the preparation of more complex alkynyl-
phosphine-boranes was briefly investigated. To this end,
readily available ferrocene, benzo-15-crown-5 ether, and
leucine derived copper acetylides 11, 13, and 15 were reacted
with dicyclohexylphosphine-borane 7a under our standard
conditions (Scheme 2). Except in the case of 13, which gave
the corresponding alkynylphosphine-borane 14 in a modest
39% yield, 11 and 15 were smoothly transformed to the
corresponding alkynylphosphine-boranes 12 and 16 with
high efficiency, therefore demonstrating further the syn-
thetic utility of our procedure. The stereochemical outcome
of the oxidative alkynylation was also addressed starting
from optically enriched phosphine-borane 18 (85% ee).4
Upon reaction with phenylethynylcopper 17, a clean alky-
nylation occurred with retention of configuration, yielding
enantiomerically enriched alkynylphosphine-borane 19
(82% ee), with almost no erosion of optical purity.
Acknowledgment. Our work was supported by the Uni-
ꢀ
ꢀ
versite Libre de Bruxelles, the Universite de Versailles
Saint-Quentin-en-Yvelines, the CNRS, the FNRS
(Incentive Grant for Scientific Research No. F.4530.13),
ꢀ
the Region Basse-Normandie, and the European Union
(FEDER Funds). COST ACTION CM0802 “PHOSCI-
NET” isalsoacknowledged for support. K.J., R.V., and C.
ꢁ
T. respectively acknowledge the Ministere de la Recherche
and the Fonds pour la formation a la Recherche dans
ꢁ
l’Industrie et dans l’Agriculture (F.R.I.A.) for graduate
fellowships. Mr. Gilbert Duhirwe (ULB) is also acknowl-
edged for technical assistance.
The scale-up of the reaction and the postfunctionaliza-
tion of alkynylphosphine-boranes was finally evaluated
(Scheme 3). Indeed, we could demonstrate that the reac-
tion is not limited to the small scale (0.24 mmol) used for
Supporting Information Available. Experimental pro-
1
cedures, characterization, copies of H and 13C NMR
(14) (a) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5,
2315. (b) Li, Y.; Das, S.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem.
Soc. 2012, 134, 9727.
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) (a) Brisset, H.; Gourdel, Y.; Pellon, P.; Le Corre, M. Tetrahedron
Lett. 1993, 34, 4523. (b) Uziel, J.; Darcel, C.; Moulin, D.; Bauduin, C.;
ꢀ
Juge, S. Tetrahedron: Asymmetry 2001, 12, 1441.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX