A superior method for the reduction of secondary phosphine oxides

Article abstract of DOI:10.1021/ol0517832

(Chemical Equation Presented) Diisobutylaluminum hydride (DIBAL-H) and triisobutylaluminum have been found to be outstanding reductants for secondary phosphine oxides (SPOs). All classes of SPOs can be readily reduced, including diaryl, arylalkyl, and dialkyl members. Many SPOs can now be reduced at cryogenic temperatures, and conditions for preservation of reducible functional groups have been found. Even the most electron-rich and sterically hindered phosphine oxides can be reduced in a few hours at 50-70°C. This new reduction has distinct advantages over existing technologies.

Full text of DOI:10.1021/ol0517832

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4277-4280
A Superior Method for the Reduction of
Secondary Phosphine Oxides
Carl A. Busacca,* Jon C. Lorenz, Nelu Grinberg, Nizar Haddad, Matt Hrapchak,
Bachir Latli, Heewon Lee, Paul Sabila, Anjan Saha, Max Sarvestani, Sherry Shen,
Richard Varsolona, Xudong Wei, and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer-Ingelheim Pharmaceuticals Inc.,
900 Ridgebury Road, Ridgefield, Connecticut 06877
cbusacca@rdg.boehringer-ingelheim.com
Received July 27, 2005
ABSTRACT
Diisobutylaluminum hydride (DIBAL-H) and triisobutylaluminum have been found to be outstanding reductants for secondary phosphine oxides
(SPOs). All classes of SPOs can be readily reduced, including diaryl, arylalkyl, and dialkyl members. Many SPOs can now be reduced at
cryogenic temperatures, and conditions for preservation of reducible functional groups have been found. Even the most electron-rich and
sterically hindered phosphine oxides can be reduced in a few hours at 50−70 °C. This new reduction has distinct advantages over existing
technologies.
Secondary phosphine oxides (SPOs) are crucial building
blocks for the construction of phosphine ligands and have
also been used as ligands themselves with both actinide
metals1 and transition metals in organic synthesis.2 Secondary
phosphines are also used in SNAr, SN2, Michael addition,
hydrophosphination, and cross-coupling syntheses of tertiary
phosphines.3 We have recently patented the BIPI ligands4
(Figure 1) as electronically tunable scaffolds for asymmetric
catalysis, and these ligands have now been utilized in a
variety of asymmetric transformations.5 Retrosynthetically,
the BIPI ligands are prepared from secondary phosphines,
and we sought acceptable methods for larger scale syntheses
of this class of compounds. A survey of the literature showed
* To whom correspondence should be addressed.
(1) For examples, see: (a) Grim, S. O.; Satek, L. C. J. Inorg. Nucl. Chem.
1977, 39, 499. (b) Gatrone, R. C.; Dietz, M. L.; Horwitz, E. P. SolV. Extr.
Ion Exch. 1993, 11 (3), 411.
Figure 1. BIPI ligand retrosynthesis.
(2) (a) Li, G. Y. J. Organomet. Chem. 2002, 653 (1/2), 63. (b) Jiang,
X.-b.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.; Duchateau, A. L. L.;
Andrien, J. G. O.; Boogers, J. A. F.; de Vries, J. G. Org. Lett. 2003, 5 (9),
1503. (c) Bo¨rner, A.; Dubrovina, N. V.; Angew. Chem., Int. Ed. 2004, 43
(44), 5883.
a number of possible methods, yet none were found to be
satisfactory: SPOs can be converted to chlorophosphines and
then reduced,6 yet distillation of the intermediate chloro-
10.1021/ol0517832 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/24/2005

phosphines is required for optimum results. The high vacuum
needed to accomplish this is simply not available in a typical
pilot plant. In addition, LAH is often used for the reduction,
and this is a hazardous substance to handle on large scale.
We also wanted to avoid a two-step procedure for the
transformation. The reduction has been performed with
neutral silanes such as diphenylsilane,7 yet temperatures in
excess of 200 °C are often used. This is beyond the upper
working temperature (∼150 °C) of most types of plant
reactor systems. SPOs have been reduced with electron-
deficient silanes such as trichlorosilane, usually in refluxing
toluene or xylene, with added amines.8 Trichlorosilane has
both a low flash point (-13 °C) and low boiling point (31
°C) and is used at temperatures far above its boiling point.
This approach was therefore rejected on safety grounds.
Mechanistically, trichlorosilane is the electrophilic partner
in a nucleophilic attack by the SPO oxygen. This type of
reduction is therefore known to be quite difficult in the case
of electron-deficient phosphine oxides,9 and we were par-
ticularly interested in the reduction of these substrates. LAH
alone has also been used for this reduction,10 yet it presents
handling difficulties, is nonchemoselective, and most im-
portantly, can lead to primary phosphine impurities through
aryl C-P bond cleavage.11 The reduction of SPOs has
also been achieved with borane, in a significant advance
recently made by Pietrusiewicz.12 However, a recent severe
industrial accident with borane has been reported,13 reducing
the enthusiasm for large-scale use of this reagent which is
used in considerable excess in the reported procedure. The
latter method can also lead to significant amounts of the
borane adduct of the phosphinous acid tautomer as an
impurity.
We screened a series of commercially available reducing
agents with diphenylphosphine oxide and quickly found that
diisobutylaluminum hydride (DIBAL-H) effected clean
reduction to diphenylphosphine in minutes at ambient
temperature. This reducing agent has never been reported
for the reduction of SPOs,14 although it was reported more
than 25 years ago for the reduction of triphenylphosphine
oxide.15
DIBAL-H is an inexpensive aluminum alkyl which is
available in bulk in “process friendly” solvents such as
toluene, heptane, and THF. This is due to its central role in
the polymer industry for the production of polyethylene and
polybutadiene under Ziegler-Natta catalysis.16 We therefore
screened a series of diaryl SPOs with DIBAL-H, as shown
in Table 1. Our screening conditions used 3 equiv of DIBAL-
H/THF at ambient temperature, and all initial substrates
(entries 1-10) were reduced within the time required to reach
the spectrometer (∼10 min). The extremely electron-rich17a
p-NMe2 derivative (12, σP ) -0.83) as well as the methoxy-
substituted SPOs 13 and 14, however, all required 5 equiv
of DIBAL-H to reach completion at 25-35 °C. It seems
likely that 2 equiv of reducing agent are chelated unproduc-
tively to the heteroatoms in these species.
We next evaluated lower reaction temperatures and
reduced DIBAL-H charges. Many of the diaryl substrates
could actually be reduced between -78 and -20 °C. The
DIBAL-H charge could also be reduced to ∼1.5 equiv in
many cases, although this was ultimately found to depend
on the hydration state of the SPOs. A few of the phosphine
oxides crystallized as hydrates. We have found that both
coulometric and volumetric Karl Fisher water determinations
on SPOs are very treacherousswe routinely oberved “false
positives” for these species and subsequently found that only
TGA-IR in conjunction with DSC and elemental analysis
could reveal the true hydration state of these substrates. As
expected, the hydrates require additional DIBAL-H to effect
the reduction. We next focused on arylalkyl and dialkyl
SPOs. Phenylisopropylphosphine oxide 15 was reduced in
ca. 10 min at ambient temperature, yet phenyl-tert-butyl-
phosphine oxide 16 showed no reduction after several hours
at 25 °C. This substrate was cleanly reduced in 4 h at 50
(3) For selected examples, see the following. SNAr: (a) Williams, J. M.
J.; Coote, S. J.; Dawson, G. J.; Frost, C. G. Synlett 1993, 509. SN2: (b)
Sakai, T.; Kodama, T.; Fujimoto, T.; Ohta, K.; Yamamoto, I.; Kakehi, A.
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Roucoux, A.; Larpent, C.; Patin, H. J. Organomet. Chem. 1996, 509 (1), 9.
Hydrophosphination: (g) Shulyupin, M. O.; Kazankova, M. A.; Beletskaya,
I. P. Org. Lett. 2002, 4 (5), 761. (h) Kawaoka, A. M.; Marks, T. J. J. Am.
Chem. Soc. 2004, 126 (40), 12764. Cross-coupling: (i) Herd, O.; Hessler,
A.; Hingst, M.; Tepper, M.; Stelzer, O. J. Organomet. Chem. 1996, 522,
69. (j) Cai, D.; Payack, J. F.; Bender, D. R.; Hughes, D. L.; Verhoeven, T.
R.; Reider, P. J. J. Org. Chem. 1994, 59 (23), 7180. (k) Kraatz, H.-B.;
Pletsch, A. Tetrahedron: Asymmetry 2000, 11, 1617. (l) Hillhouse, J. H.
U. S. Pat. 5,550,295, 1996.
(4) Busacca, C. A. U. S. Pat. 6,316,620, 2001; European Patent 1218388.
Boehringer-Ingelheim Phosphinoimidazolines.
(5) (a) Busacca, C. A.; Grossbach, D.; Campbell, S. J.; Dong, Y.;
Eriksson, M. C.; Harris, R. E.; Jones, P.-J.; Kim, J.-Y.; Lorenz, J. C.;
McKellop, K. B.; O’Brien, E. M.; Qiu, F.; Simpson, R. D.; Smith, L.; So,
R. C.; Spinelli, E. M.; Vitous, J.; Zavattaro, C. J. Org. Chem. 2004, 69
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Spinelli, E. M. Org. Lett. 2003, 5 (4), 595. (c) Menges, F.; Neuburger, M.;
Pfaltz, A. Org. Lett. 2002, 4 (26), 4713. (d) Boland, N. A.; Casey, M.;
Hynes, S. J.; Matthews, J. W.; Smyth, M. P. J. Org. Chem. 2002, 67 (11),
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Hii, K. K. Tetrahedron Lett. 2003, 44 (28), 5213.
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(8) (a) Dong, X.; Erkey, C. J. Mol. Catal. A 2004, 211, 73. (b) Elding,
L. I.; Kellenberger, B.; Venanzi, L. M. HelV. Chim. Acta 1983, 66(6),
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(9) (a) Hayashi, T.; Hirate, S.; Kitayama, K.; Tsuji, H.; Torii, A.; Uozumi,
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B. Org. Lett. 2004, 6 (25), 4675.
(10) (a) Kapoor, P. N.; Venanzi, L. M. HelV. Chim. Acta 1977, 60 (277),
2824. (b) Fehring, V.; Kadyrov, R.; Ludwig, M.; Holz, J.; Haage, K.; Selke,
R. J. Organomet. Chem. 2001, 1-2, 120. (c) Miller, P. W.; Nieuwenhuyzen,
M.; Xu, X.; James, S. L. Chem. Commun. 2002, 18, 2008.
(12) Pietrusiewicz, K. M.; Stankevic, M. Synlett 2003, 7, 1012.
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Jan 13, 2004; Int. Appl. No. PCT/US05/01526.
(15) GB 1,520,237, Appl. No. 18850/77, 1977.
(16) For reviews see (a) Monakov, Y. B.; Sabirov, Z. M.; Urazbaev, V.;
Zaikov, G. E. Polymer Yearbook 2003, 18, 75. (b) Monakov, Y. B.; Sabirov,
Z. M.; Zaikov, G. E. New. DeV. Chem. Biochem. 2003, 53. See also (c)
Natta, G.; Mazzanti, G.; Giorgio, D.; Gino, S.; Sartori, G.; Motroni, G. IT
Pat. 718796, 1966. (d) Ziegler, K. Chem. Ber. 1964, 76, 545.
(17) (a) Hansch, C.; Leo, A.; Unger, S. H.; Kim, N. H.; Nikaitani, D.;
Lien, E. J. J. Med. Chem. 1973, 16 (11), 1207. (b) 31P NMR δ -123 ppm,
(11) Treatment of (3,5-F2-C6H3)2POH with LAH from 0 to 25 °C leads
to a mixture of the desired secondary phosphine and 3,5-difluorophe-
1
1
nylphosphine, 31P NMR δ -121 ppm, t, JP-H ) 203 Hz.
t, JP-H ) 206 Hz.
4278
Org. Lett., Vol. 7, No. 19, 2005

Table 1. Reduction of Secondary Phosphineoxides by DIBAL-H and i-Bu3Al
entry
R1
SPO
R2
time/T (°C)
Al speciesa
R1R2PH
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
C6H5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
7
C6H5
10 min/25
10 min/25
10 min/25
10 min/25
10 min/25
10 min/25
10 min/25
10 min/25
1 h/-20
1 h/-20
8 h/25
45 min/25c
40 min/25c
8 h/35c
10 min/25
4 h/50
1 h/25
4 h/50
4 h/50
15 min/25
30 min/25
30 min/25
24 h/70e
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
T
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
28
28
42
86
90
83
80b
89
81
82
90
90
80
80
92
91
75
90
86
85
88
87
72
82
81
75
4-F-C6H4
4-Cl-C6H4
4-Me-C6H4
3-F-C6H4
3-Cl-C6H4
3-F, 5-Me-C6H3
3,5-F2, 4-OMe-C6H2
3,5-Cl2-C6H3
3,5-F2-C6H3
2-Me-C6H4
4-NMe2-C6H4
4-OMe-C6H4
2-OMe-C6H4
C6H5
C6H5
n-Bu
4-F-C6H4
4-Cl-C6H4
4-Me-C6H4
3-F-C6H4
3-Cl-C6H4
3-F, 5-Me-C6H3
3,5-F2, 4-OMe-C6H2
3,5-Cl2-C6H3
3,5-F2-C6H3
2-Me-C6H4
4-NMe2-C6H4
4-OMe-C6H4
2-OMe-C6H4
i-Pr
t-Bu
n-Bu
C6H11
t-Bu
C6H11
t-Bu
3,5-(CF3)2-C6H3
3-F, 5-Me-C6H3 + PhId
3-F, 5-Me-C6H3 + PhCONMe2
2,4,6-Me3-C6H2
3,5-(CF3)2-C6H3
3-F, 5-Me-C6H3 + PhId
3-F, 5-Me-C6H3 + PhCONMe2
2,4,6-Me3-C6H2
d
d
7
21
T
T
a D ) DIBAL-H; T ) i-Bu3Al. b Yield of phosphine borane complex. c 5 equiv of DIBAL-H was used. d Competition experiment. e 8 equiv of i-Bu3Al
was used.
°C, however. The result underscores the role of sterics in
also be used at somewhat elevated temperatures. Entries 21-
23 of Table 1 show reductions with i-Bu3Al (TIBA).
the DIBAL-H reduction. Di-n-butylphosphine oxide and
dicyclohexylphosphine oxide (entries 17 and 18) were readily
reduced at 25 and 50 °C, respectively. We next examined
di-tert-butylphosphine oxide 19, certainly one of the most
electron-rich and sterically hindered SPOs known. In 4 h at
50 °C, complete reduction to the secondary phosphine was
observed. The substrate scope of this new reduction is clearly
quite broad.
The reduction of 3,5-bis-CF3-substituted SPO 20 requires
special comment. When this reduction was attempted with
DIBAL-H in THF, long reaction times at -78 °C were
required to minimize formation of the primary phosphine,17b
which arose by aryl C-P cleavage. This substrate is the most
electron deficient17a (2σM ) +0.86) of the entire series and
the only substrate where primary phosphine impurities
were ever observed. A remarkable solvent effect was
subsequently uncovered, however; DIBAL-H in hydrocar-
bons gave rapid reduction at 23 °C with no primary
phosphine formation.
Figure 2. Additional organoaluminum reductants.
In addition to diisobutylaluminum hydride, several other
organoaluminums were found to be capable of effecting the
reduction of SPOs (Figure 2). Triisobutylaluminum and
triisobutyldialuminoxane are both competent reductants in
the range of 25-70 °C, and tetraisobutyldialuminoxane can
Two competition experiments (21,22) showed that both
amide and aryl iodide functionality are preserved during the
SPO reductions with i-Bu3Al. In addition, entries 13 and 14
have established that ethers are similarly unaffected by
Org. Lett., Vol. 7, No. 19, 2005
4279

DIBAL-H at ambient temperature, despite the susceptibility
of ethers to this reductant at elevated temperatures.18 Entry
23 is significant, as the exceedingly hindered mesityl SPO
21 was reduced in toluene in 24 h at 70 °C. A solvent study
revealed an acceleleration of the SPO reduction rate by i-Bu3-
Al when toluene was used, rather than THF. It is noteworthy
that the very hindered phosphines 40 and 42 have not been
synthesized previously by direct reduction of their oxides.
Secondary phosphines are extremely air-sensitive com-
pounds, and the electron-rich varieties oxidize very rapidly
when exposed to air. For this reason, we developed several
interlocking strategies for reaction workup to minimize
inadvertent oxidation of the products. First, a water-im-
miscible solvent, such as MTBE (methyl tert-butyl ether) is
added and the cooled reaction mixture then quenched with
aqueous NaOH while sparging with argon. This results in
two clear phases free of any solids or gels, as the aluminum
hydroxide byproduct is solubilized by base. For small-scale
reactions, the phase separation could conveniently be per-
formed in the body of a 50 mL syringe using a ∼15 cm
long needle. The organic phase was then transferred to an
inerted Airfree18 filter containing MgSO4, connected to a
recovery flask.19 For larger scale reactions, we used a
jacketed flask with a bottom drain valve. At still greater scale,
the organic phase was dried by azeotropic distillation. In this
way, dry solutions of secondary phosphines ready for further
transformation were conveniently obtained. Many solvents
in addition to THF can be used for the SPO reduction
including toluene, heptane, cyclohexane, methyl-THF, and
CH2Cl2.
The mechanism of the DIBAL-H reduction of SPOs is
not yet clear. The “expected” acid-base reaction between
the two components would generate H2 and intermediate 43,
as shown in Figure 3. A gas is indeed evolved when the
Figure 3. Possible reaction intermediates.
two reagents are combined. However, GC analysis of this
gas shows it contains both H2 and isobutane, suggesting the
potential intermediacy of species 44 (Figure 3). The mech-
anism of this reduction is under intense scrutiny and will be
reported elsewhere shortly along with full calorimetric
analyses.
In summary, a new reduction of secondary phosphine
oxides using neutral organoaluminums has been discovered.
The reaction is extremely broad in scope, can be performed
at moderate temperatures, is operationally simple, and
provides secondary phosphines in high yields and purities.
Supporting Information Available: Synthetic details,
characterization of all species, and digital photographs of
glassware setups are provided. This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) Chemglass Catal. No. AF-0542-22; AF-0542-25.
(19) Photographs of the glassware are found in the Supporting Informa-
tion.
OL0517832
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Org. Lett., Vol. 7, No. 19, 2005