Ambient temperature hydrophosphination of internal, unactivated alkynes and allenyl phosphineoxides with phosphine borane complexes

Article abstract of DOI:10.1021/ol9022547

[Chemical Equation Presented] Phosphine boranes have been found to hydrophosphinate Internal, unactivated alkynes at room temperature under basic conditions without the need for catalysts or radical initiators. The use of air-sensitive secondary phosphine

Full text of DOI:10.1021/ol9022547

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5594-5597
Ambient Temperature
Hydrophosphination of Internal,
Unactivated Alkynes and Allenyl
Phosphineoxides with Phosphine
Borane Complexes
Carl A. Busacca,* Elisa Farber, Jay DeYoung, Scot Campbell, Nina C. Gonnella,
Nelu Grinberg, Nizar Haddad, Heewon Lee, Shengli Ma, Diana Reeves,
Sherry Shen, and Chris H. Senanayake
Departments of Chemical DeVelopment and Analytical Sciences, Boehringer-Ingelheim
Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877
carl.busacca@boehringer-ingelheim.com
Received September 30, 2009
ABSTRACT
Phosphine boranes have been found to hydrophosphinate internal, unactivated alkynes at room temperature under basic conditions without
the need for catalysts or radical initiators. The use of air-sensitive secondary phosphines is avoided in this facile process. Broad scope in
both the phosphine borane and alkyne partners leads to excellent diversity in the phosphine products. Asymmetric hydrogenation of these
species then provides one of the shortest possible routes to chiral monodentate phosphines. Hydrophosphination of allenyl phosphine oxides
under similar conditions followed by hydrogenation of the exomethylene moiety yields a wide variety of bis-phosphine derivatives.
We have recently reported on the use of BIPI 153, a novel
P-N ligand capable of carrying out asymmetric hydrogena-
tions with near-perfect enantioselectivity.1 The key C-P
bond-forming reaction in the synthesis of this chiral ligand
is an SNAr reaction between fluoroimidazoline 1 and a
phosphine borane (Figure 1). As part of a continuing
investigation of conformational restriction in these ligands,
we prepared alkynyl fluoroimidazoline 2 and subjected it to
our standard SNAr conditions. To our surprise, no trace of
the expected product was found; rather, a vinylphosphine
borane 3 (Scheme 1) was generated via regiospecific hy-
drophosphination of the internal alkyne.2 The regiochemistry
and stereochemistry of 3 were easily established through the
application of two successive heteronuclear NOE (HOESY)
experiments with 19F and 31P, respectively.3 It was quickly
determined that neither the fluorine or imidazoline moieties
(1) (a) Busacca, C. A.; Lorenz, J. C.; Grinberg, N.; Haddad, N.; Lee,
H.; Li, Z.; Liang, M.; Reeves, D.; Saha, A.; Varsolona, R.; Senanayake,
C. H. Org. Lett. 2008, 10, 341. (b) Busacca, C. A.; Lorenz, J. C. WO Pat.
Appl. 2008067218. PCT/US07/85165.
(2) For reviews, see: (a) Delacroix, O.; Gaumont, A.-C. Curr. Org.
Chem. 2005, 9, 1851. (b) Coudray, L.; Montchamp, J.-L. Eur. J. Org. Chem.
2008, 3601. (c) Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A.
Eur. J. Org. Chem. 2006, 29.
10.1021/ol9022547  2009 American Chemical Society
Published on Web 11/12/2009

Phosphine boranes have been added to terminal alkynes
under thermal7a and palladium-catalyzed7b conditions, yet
additions to internal, unactivated alkynes of the current work
have not been previously reported. Secondary phosphine
oxides have also been utilized for the hydrophosphination
of alkynes using both thermal4e and metal-catalyzed8a,b
methods, as have H-phosphinates,8c yet these of course
require a subsequent reduction to yield the desired phos-
phines.
Figure 1. BIPI 153 and SNAr substrate.
We established a single experimental protocol for the
hydrophosphinations and applied it to all substrates. We used
the conditions previously optimized for the SNAr reaction,
namely NaH (60% in oil, untreated) in DMAc at ambient
temperature. A finding of considerable practical importance
was made during the course of this work which led to a key
modification for the reaction protocol. We discovered that
phosphine borane anions such as those prepared here will
oxidize in air to phosphinous acid boranes. These organo-
phosphorus species have been previously described, prepared
by reduction of secondary phosphine oxides with borane.9
This oxidation has been achieved with N2O,10 yet we are
unaware of any reports describing this air oxidation. Scheme
2 shows the chemical shifts of all relevant species as
were required for reactivity, as diphenylacetylene gave the
product of internal hydrophosphination 4 under the same
conditions (Scheme 1).
Scheme 1. Alkyne Hydrophosphinations
The addition of free secondary phosphines to alkynes has
been known for more than 40 years4 and continues to be a
method used for the synthesis of vinyl phosphines.4d Hy-
drophosphination of alkynes with secondary phosphines has
also been accomplished with catalysis by various transition
metals,5 and silylphosphines have been similarly utilized.6a
From the point of view of process safety and raw material
handling, however, the ability to utilize an air-stable phos-
phine borane6b in a process rather than a pyrophoric free
phosphine confers an enormous advantage. All of the
hydrophosphinations described here proceed without the need
for catalysis or the use of pyrophoric materials, and can even
be performed with catalytic base.6c Here the presumed vinyl
anion intermediate likely deprotonates the phosphine borane
starting material.
Scheme 2. Oxidation and NMR Shifts
determined by 31P NMR spectroscopy. Under the basic
conditions of the hydrophosphination (and the ligand SNAr
reactions), the anion (8) of the phosphinous acid borane is
ultimately formed. We therefore changed our experimental
protocol: The phosphine borane, alkyne, and DMAc were
first charged to the reactor, and then argon or nitrogen was
bubbled beneath the solution surface for 15 min prior to the
addition of NaH, which initiates the hydrophosphination. This
serves to remove dissolved oxygen and allowed us to reduce
the phosphine borane charge from 2 equiv to 1.2 equiv. This
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Org. Lett., Vol. 11, No. 24, 2009
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Table 1. Hydrophosphination of Internal Alkynes*
* All reactions at rt. All reactions with 1 equiv of alkyne, 1.2 equiv of phosphine borane, 1.2 equiv of 60% NaH/oil, in DMAc, unless otherwise noted.
Average concentrations: [0.47 M] (PB), [0.35 M] (alkyne). a Isolated yield (E + Z) after crystallization and/or chromatography. b Overall E/Z ratio after
purification. c 1.5 equiv of phosphine borane used. d 2.0 equiv of phosphine borane used.
phosphine borane anion oxidation is also the explanation
behind the unusual stoichiometric requirements for the
original ligand SNAr reaction previously noted.1a
With the experimental procedure thus established, we set
out to determine the scope with respect to both the secondary
phosphine borane and the internal alkyne. The results
obtained using eight different alkynes and seven different
phosphine boranes are shown in Table 1.
Phenylalkylalkynes were found to react with a variety of
phosphine boranes at room temperature, furnishing products
9-13. The sterically demanding di-tert-butyl- and m-
xylylphosphine boranes reacted readily, as did diphenyl
phospholane phosphine borane (12 and 13). In general,
mixtures of E and Z olefins were obtained, with the E by far
the major (or exclusive) isomer formed.
We then examined diphenylacetylene, and vinyl phosphine
boranes 14-16 were all prepared in good yield from this
alkyne. Five additional diarylacetylenes were then examined,
providing products 17-22.
We found that the presence of a single electron-withdraw-
ing substituent on a nonsymmetric diarylacetylene was
sufficient to give high regiocontrol (20, 22) for the addition.
The bis(o-tolyl)acetylene was prepared, and it was found to
react efficiently with dicyclohexyl phosphine borane to
furnish 21 in excellent yield. We carried out this experiment
specifically because this substrate was reported4f to be
unreactive toward a free secondary phosphine. Thus the
current protocol not only provides a safer and more
convenient experimental method, but also gives access to
targets that cannot be prepared by other approaches.
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Org. Lett., Vol. 11, No. 24, 2009

We have also examined the reactivity of allenyl phosphine
oxides 23 and 24, which were each prepared in one step by
a well-established propargylic rearrangement reaction.12 Each
of these extremely reactive substrates was hydrophosphinated
(Scheme 3) in minutes at -35 °C furnishing the mixed
Scheme 4. Vinylphosphine Functionalizations
Scheme 3. Synthesis of Bisphosphines
(+)-33 in >99% ee. The synthesis and use of chiral
monodentate phosphines has become an extremely active
area of recent research with applications to many different
types of asymmetric transformations.15 The hydrophosphi-
nation/hydrogenation sequence described here provides one
of the shortest possible routes to these targets. Hydrogenation
of 27, 25, and 32 with tricyclohexylphosphine as ligand
furnished bis-phosphines 34, 35, and 36, respectively. In each
case, a single species was observed by NMR, showing that
the hydrogenations had proceeded with complete control of
the relative stereochemistry to give the trans-species shown
(Scheme 4). Since dialkyl- and diaryl-substitution on phos-
phorus is tolerated for both the allene synthesis and the
hydrophosphination, broad diversity in the substituents on
each phosphorus atom can be achieved.
In summary, we have discovered that phosphine borane
anions will hydrophosphinate internal unactivated alkynes
and allenyl phosphine oxides at ambient temperature or
below, without the need for catalysts, radical initiators, or
microwave heating. The former class of vinylphosphine
boranes can be hydrogenated to optically pure monodentate
phosphines, while the latter class can be converted stereo-
selectively to bis-phosphine derivatives. The reactions utilize
easily handled and stable phosphine boranes, and show good
scope with respect to both the multiple bond electrophile
and phosphine borane partners. The creation of chiral
monodentate phosphine libraries for screening in asymmetric
catalysis as well as performing the allene hydrophosphina-
tions with control of the absolute stereochemistry are under
active investigation and will be reported in due course.
phosphine oxide-phosphine boranes 25-32 in good yield.
We switched the solvent from DMAc to DMF here to take
advantage of the lower freezing point of the latter. Hydro-
phosphination of allenes with hypophosphorous acids13 and
secondary phosphines5d are known. No examples of allene
hydrophosphination with phosphine boranes have been
previously reported.
These mixed species should be quite valuable synthetically.
Deprotection of the phosphine borane would furnish a bis-
phosphine monooxide (BPMO), a class of ligands for a
variety of metal-catalyzed reactions14 which have been the
subject of several recent reviews.14a,d Reduction of the
phosphine oxide would yield a bis-phosphine, and these are
probably the single most important class of bidentate ligands
in all of catalysis.
To demonstrate the utility of these novel phosphine
intermediates for the development of a unique family of
phosphine ligands for many catalytic processes, we first
screened a number of hydrogenation conditions for our vinyl
phosphine boranes. A Rh-(R,R)-Skewphos catalyst system
was identified as suitable for olefin reduction without
disturbing the phosphine borane (Scheme 4). Applying this
hydrogenation to 15 furnished chiral phosphine borane (R)-
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Supporting Information Available: Full experimental
procedures and compound characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
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