Hydrophosphination of propargylic alcohols and amines with phosphine boranes

Article abstract of DOI:10.1021/ol400309y

The first uncatalyzed hydrophosphinations of propargylic amines and alcohols with phosphine- borane complexes are described. The reactions proceed at ambient temperature or below without the use of protecting groups or the need to handle pyrophoric second

Full text of DOI:10.1021/ol400309y

ORGANIC
LETTERS
2013
Vol. 15, No. 5
1132–1135
Hydrophosphination of Propargylic Alcohols
and Amines with Phosphine Boranes
†
Carl A. Busacca,* Bo Qu, Elisa Farber, Nizar Haddad, Nicole Gret, Anjan K. Saha,
ꢀ
Magnus C. Eriksson, Jiang-Ping Wu, Keith R. Fandrick, Steve Han, Nelu Grinberg,
Shengli Ma, Heewon Lee, Zhibin Li, Michael Spinelli, Austin Gold, Guijun Wang,‡
Peter Wipf,† and Chris H. Senanayake
Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury
Road, Ridgefield, Connecticut 06877, United States, Department of Chemistry,
Center for Chemical Methodologies and Library Development, University of Pittsburgh,
219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States, and
Department of Chemistry and Biochemistry, Old Dominion University,
4541 Hampton Boulevard, Norfolk, Virginia 23529, United States
carl.busacca@boehringer-ingelheim.com
Received February 4, 2013
ABSTRACT
The first uncatalyzed hydrophosphinations of propargylic amines and alcohols with phosphineꢀ borane complexes are described. The reactions
proceed at ambient temperature or below without the use of protecting groups or the need to handle pyrophoric secondary phosphines, furnishing
air-stable phosphineboraneꢀamines and alcohols in good yields. Utilization of chiral propargylic substrates and unsymmetrical secondary
phosphineboranes leads to diastereomeric P-chiral products that can be separated by fractional crystallization or chromatography. Initial
applications of these new PꢀX species to asymmetric catalysis are detailed.
Phosphines are the pre-eminent class of ligands to
transition metals, and broad applications of phosphines
in asymmetric catalysis have been realized in the past
30 years.1 We have recently described the facile uncata-
lyzed hydrophosphination of unactivated alkynes with the
anions of phosphineboranes.2 This methodology also con-
veniently avoids the use of pyrophoric free phosphines.
The analogous hydrophosphination of propargylic sub-
strates, if realized, would provide access to functionalized
allylic systems bearing a heteroatom and substituted by a
phosphine.
Direct treatment of phenylpropynol1 withdicyclohexyl-
phosphine borane 2 in DMF at ambient temperature with
60% NaH (2 equiv) was found to generate the desired
phosphineboraneꢀallylic alcohol 3 in 90% yield as a single
stereoisomer after 18 h reaction time at 20 °C and recrys-
tallization (Scheme 1). It is significant to note that no protec-
tion of the alcohol was required. Chiral ynol (S)-(ꢀ)-4
reacted similarly, with formation of enantiomerically pure,
crystalline vinylphosphine borane (S)-5 in 83% yield after
3 h reaction time. In all of the cases described herein, the
Z hydrophosphination product was the major or exclusive
isomer formed. This result differs from those results ob-
tained with alkynes lacking the alcohol functionality,
all of which gave predominately E isomers.2 (S)-4 also
† University of Pittsburgh.
‡ Old Dominion University.
(1) For reviews, see: (a) Collman, J. P.; Hegedus, L. S.; Norton, J. R.;
Finke, R. G. Principles and Applications of Organotransition Metal
Chemistry; University Science Books: Mill Valley, CA, 1987; pp 21ꢀ56.
(b) Busacca, C. A.; Senanayake, C. H. The Use of New Phosphines as
Powerful Tools in Asymmetric Synthesis of Biologically Active Compounds.
In Comprehensive Chirality; Carreira, E. M., Yamamoto, H., Eds.; Elsevier:
Amsterdam, 2012; Vol. I, pp 167ꢀ216. (c) Luhr, S.; Holz, J.; Borner, A.
ChemCatChem 2011, 3, 1708–1730. (d) van Leeuwen, P. W. N. M.; Freixa,
Z.; Zuidema, E. Properties of Phosphorus Ligands. In Phosphorus Ligands in
€
€
€
Asymmetric Catalysis; Borner, A., Ed.; Wiley-VCH: Weinheim, 2008; pp
1433ꢀ1454. (e) Stelzer, O.; Rossenbach, S.; Hoff, D.; Schreuder-Goedheijt,
M.; Kamer, P. C. J.; Reek, J. N. H.; van Leeuwen, P. W. N. M. Ligands:
Phosphorus-Containing Ligands. In Multiphase Homogeneous Catalysis;
€
Borner, A., Ed.; Wiley-VCH: Weinheim, 2005; pp 66ꢀ82.
(2) Busacca, C. A.; Farber, E.; DeYoung, J.; Campbell, S.; Gonnella,
N. C.; Grinberg, N.; Haddad, N.; Lee, H.; Ma, S.; Reeves, D.; Shen, S.;
Senanayake, C. H. Org. Lett. 2009, 11, 5594–5597.
r
10.1021/ol400309y
Published on Web 02/21/2013
2013 American Chemical Society

reacted smoothly with dicyclohexylphosphine borane 2,
giving adduct (S)-5 in 83% yield after 3 h at ambient
temperature (Scheme 1). The less sterically demanding
diethylphosphine borane gave (S)-7 as a 2:1 Z/E mixture.
Mechanistically, these results imply that the regio- and
stereoselectivity of the hydrophosphination islikely mainly
a consequence of the attractive electrostatic interactions,
first between alkoxide and phosphine borane, and fol-
lowedby coordination between thealkoxide sodium cation
and the vinyl anion intermediate.
Scheme 1. Hydrophosphination of Propargylic Alcohols
Figure 1. Crystal Structures of (ꢀ)-9c (left) and 12 (right).
Scheme 2. Hydrophosphination with PhCyPHꢀBH3
X-ray crystal structures.3 Itshould be noted that no borane
transfer to the amine center occurred.
The olefin geometry was assigned by 31P HOESY
experiments.5 Reaction of bis-t-Bu phosphine borane 6
furnished a 63% yield of adduct 12, as a crystalline solid
and as a single isomer (E), after only 30 min at rt. The
structure of 12 is shown in Figure 1. Phosphine borane 13
gave adduct 14 in high yield as a 3.3: 1 E: Z-mixture, after
the same reaction time. The isomers proved to be readily
separable, and both were crystalline as well.
The reaction of a nonsymmetric phosphine borane,
cyclohexylphenylphosphine borane 8, with (S)-(ꢀ)-4 was
examined next, and the diastereomeric products 9c and 9d
were produced in 78% yield after 2 h at rt (Scheme 2). The
diastereomers were readily separated by fractional crystal-
lization to give P-chiral-(ꢀ)-9c and (þ)-9d as white solids.
The relative configuration at the phosphorus center for
these two products was first assigned by VCD,3 and the
stereochemistry then confirmed by a crystal structure of
(ꢀ)-9c (Figure 1). Compound 9c, with the RP stereochem-
istry, was the less soluble and higher melting isomer.
Propargylamines4 were found to be even more reactive.
Addition of phosphine borane 2 to (S)-10 gave the PꢀN
adduct in good yield after just 15 min at 0 °C (Scheme 3),
again without the use of protecting groups. The stereo-
chemistries of 10 and 11 were each determined through
Scheme 3. Hydrophosphinations of Propargylamine 10
(3) See the Supporting Information.
(4) For reviews on chiral propargylamines, see: (a) Zani, L.; Bolm, C.
Chem. Commun. 2006, 4263–4275. (b) Blay, G.; Monleon, A.; Pedro, J. R.
Curr. Org. Chem. 2009, 13, 1498–1539. See also: (c) Marshall, J. A.; Wolf,
M. A. J. Org. Chem. 1996, 61, 3238–2339. (d) Ding, C.-H.; Chen, D.-D.;
Luo, Z.-B.; Dai, L. X.; Hou, X.-L. Synlett 2006, 8, 1272–1274. (e)
Aschwanden, P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett. 2006, 8,
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A.; Singh, V. K. Org. Lett. 2006, 8, 2405–2408. (h) Lo, V. K.; Kung, K. K.;
Wong, M.; Che, C. J. Organomet. Chem. 2009, 694, 583–591. (i) Koradin,
C.; Gommermann, N.; Polborn, K.; Knochel, P. Chem.;Eur. J. 2003, 9,
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The nitrogen atom of the propargylamine can also be
part of a heterocycle. Alkynylimidazoline 15 underwent
hydrophosphination, as shown in Scheme 4. Reaction with
dicyclohexylphosphine borane 2 gave chiral phosphino-
imidazoline6 species 16, formed with high E selectivity.
(5) For a review, see: (a) Pregosin, P. S.; Kumar, P. G. A.; Fernandez, I.
Chem. Rev. 2005, 105, 2977. See also: (b) Bauer, W. Magn. Reson. Chem.
1996, 34, 532–537. (c) Pregosin, P. S.; Fernandez, I. Magn. Reson. Chem.
2006, 44, 76. (d) Hughes, R. P.; Zhang, D.; Ward, A. J.; Zakharov, L. N.;
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Org. Lett., Vol. 15, No. 5, 2013
1133

Deboronation and acylation (no glovebox needed) then
provided the first member of a new class of ligands,
HPN-6. Ligand HPN-7 was prepared analogously.
Scheme 4. Hydrophosphinations of Alkynylimidazolines
Figure 3. Asymmetric hydrogenations.
in good agreement with related platinum complexes.7a,c,8
Reaction of the same intermediate with the spin 1/2
nucleus 103Rh gave complex [15N]-17b. The CCS values
for this complex were ꢀ30 and þ85 ppm (15N, 31P). Both
nuclei again showed coupling to the metal, with 1J values
of 11 and 169 Hz for 15N and 31P, consistent with known
rhodium complexes.9 The combination of pronounced
CCS values and significant scalar couplings establishes a
bidentate chelation mode of these new PꢀN ligands.
HPN-6 and HPN-7 bear a resemblance to BIPI ligands
which have been used for highly enantioselective hydro-
genations,10 with the important exception of their central
alkene moiety. It was unclear whether the presence of the
olefin would prove detrimental to catalysis. The cationic
iridium BArF complexes of each ligand were prepared, in
concert with the pioneering work of Pfaltz et al. on iridium
complexes.11 Asymmetric hydrogenations (AH) of several
different olefin substrates demonstrated the competency
of these ligands in catalytic transformations. Reduction of
R-methylstilbene with the Ir complex of HPN-6 under just
1 bar of H2 gaveadduct 18in a promising 70% ee, while the
HPN-7 Ir complex furnished the target (100%) with a high
selectivity of 95% ee under the same conditions (Figure 3).
Figure 2. [15N]-Labeled metal complexes.
For applications of the new PꢀN species to catalysis, it
was necessary to establish whether they could achieve a
bidentate chelation mode to transition metals. The syn-
thesis of aminophosphine borane E-14 was thus repeated
(Scheme 3) with [15N]-aniline to give the isotopically
labeled species [15N]-E-14. This compound was then de-
boronated and the free aminophosphine exposed to 1 equiv
of 195Pt, a spin 1/2 nucleus, to give the metal complex [15N]-
ꢀ
(8) (a) Pazderski, L.; Tousek, J.; Sitkowski, J.; Kozerski, L.; Szzyk, E.
17a (Figure 2). The complex was analyzed by 15N and 31
NMR. The coordination chemical shifts (CCS: δ complex
P
ꢀ
Magn. Reson. Chem. 2007, 45, 1059–1071. (b) Schenetti, L.; Mucci, A.;
Longato, B. J. Chem. Soc., Dalton Trans. 1996, 3, 299–303. (c) Schenetti,
L.; Bandoli, G.; Dolmella, A.; Trovo, G.; Longato, B. Inorg. Chem.
1994, 33, 3169–3176.
δ free ligand) of 15N and 31P wereꢀ41and þ74 ppm, respec-
tively. The shielding of 15N and deshielding of 31P are well-
precedented phenomena in metal complexes.7 Both 15N
and 31P of complex 17a showed coupling to platinum, with
1J values of 298 and 3791 Hz, respectively. These values are
ꢀ
(9) Pazderski, L.; Tousek, J.; Sitkowski, J.; Kozerski, L.; Marek, R.;
Szzyk, E. Magn. Reson. Chem. 2007, 45, 24–36.
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(10) (a) Busacca, C. A.; Qu. B.; Gret, N.; Fandrick, K. R.; Saha, A. K.;
Marsini, M.; Reeves, D.; Haddad, N.; Eriksson, M.; Wu, J.-P.; Grinberg,
N.; Lee, H.; Li, Z.; Lu, B.; Chen, D.; Hong, Y.; Senanayake, C. H. Adv. Syn.
Catal. 2013, 355, in press. (b) Busacca, C. A.; Lorenz, J. C.; Saha, A. K.;
Cheekoori, S.; Haddad, N.; Reeves, D.; Lee, H.; Li, Z.; Rodriguez, S.;
Senanayake, C. H. Cat. Sci. Technol. 2012, 2, 2083–2089. (c) Busacca, C. A.;
Lorenz, J. C. Electronically tuned ligands for asymmetric hydrogenation.
U.S. Pat. 7,994,335, 2011. (d) Lorenz, J. C.; Busacca, C. A.; Feng, X.; Grinberg,
N.; Haddad, N.; Johnson, J.; Kapadia, S.; Lee, H.; Saha, A.; Sarvestani, M.;
Spinelli, E. M.; Varsolona, R.; Wei, X.; Zeng, X.; Senanayake, C. H. J. Org.
Chem. 2010, 75, 1155–1161. (e) 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, 341–344.
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ꢀ
Kozerski, L.; Tousek, J.; Marek, R. Magn. Reson. Chem. 2006, 44, 163–170.
ꢀ
(b) Pazderski, L.; Tousek, J.; Sitkowski, J.; Kozerski, L.; Szzyk, E. Magn.
Reson. Chem. 2007, 45, 1059–1071. (c) Busacca, C. A.; Grossbach, D.;
Campbell, S. J.; Dong, Y.; Eriksson, M. C.; Harris, R. E..; et al. J. Org.
Chem. 2004, 69, 5187–5195. (d) Schenetti, L.; Mucci, A.; Longato, B.
J. Chem. Soc., Dalton Trans. 1996, 3, 299–303. (e) Schenetti, L.; Bandoli,
G.; Dolmella, A.; Trovo, G.; Longato, B. Inorg. Chem. 1994, 33, 3169–3176.
Phosphorus: (f) 31P and 13C NMR of Transition Metal Phosphine Complexes;
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Org. Lett., Vol. 15, No. 5, 2013

Tetrasubstituted olefins were also hydrogenated with these
new catalysts. Reduction of dimethylindene under 1 bar of
H2 with the more electron-rich iridium complex HPN-7
gave product 19 with 87% ee. Hydrogenation of phenyl-
methylindene with the same catalyst gave the reduced
product 20 in 91% ee. The highest selectivity reported to
date for this challenging substrate is 96% ee (with incom-
plete conversion).12 This new hydrophosphination chem-
istry can thus clearly be used to access novel and valuable
chiral ligands for asymmetric catalysis.
boranes have been explored. The reactions proceed under
mild conditions in a transformation with good scope with
respect tobothcoupling partners. Preliminaryapplications
of two of these synthetically easily accessible catalysts,
HPN-6 and HPN-7, in asymmetric hydrogenation have
been successfully demonstrated, and further exploration of
these new P-X systems in catalytic asymmetric methodol-
ogies is now in progress.
Supporting Information Available. Experimental pro-
cedures, compound characterization, and chiral HPLC
analyses. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, the first uncatalyzed hydrophosphina-
tions of propargylic alcohols and amines with phosphine
(12) Schrems, M. G.; Neumann, E.; Pfaltz, A. Angew. Chem. 2007,
119, 8422–8424. Angew. Chem., Int. Ed. Engl. 2007, 46, 8274–8276.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 5, 2013
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