Reduction of phosphinites, phosphinates, and related species with DIBAL-H

Article abstract of DOI:10.1055/s-0028-1087671

Diisobutylaluminium hydride has been found to be an excellent reducing agent for phosphinites, phosphinates, and chlorophosphines. By performing reductions in situ, direct synthesis of secondary phosphine boranes from Grignard reagents has been achieved without isolation or purification of any intermediates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087671

LETTER
287
Reduction of Phosphinites, Phosphinates, and Related Species with DIBAL-H
R
eduction of Pho
a
sphinites
a
n
d Phosp
l
hinates A. Busacca,* Teresa Bartholomeyzik, Sreedhar Cheekoori, Ravinder Raju, Magnus Eriksson, Suresh Kapadia,
Anjan Saha, Xingzhong Zeng, Chris H. Senanayake
Department of Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA
E-mail: carl.busacca@boehringer-ingelheim.com
Received 1 September 2008
–
OEt
P
BH3
H
1) DIBAL-H (2.2 equiv)
1 h, 50 °C, PhMe
Abstract: Diisobutylaluminium hydride has been found to be an
excellent reducing agent for phosphinites, phosphinates, and chlo-
rophosphines. By performing reductions in situ, direct synthesis of
secondary phosphine boranes from Grignard reagents has been
achieved without isolation or purification of any intermediates.
P+
2) BH3 (1.1 equiv), 23 °C
90% overall yield
1
2
Key words: phosphorus, phosphines, phosphine boranes, reduc-
tions
Scheme 1
We wanted to examine a dialkylphosphinite next. Since
none are commercially available, we treated ethyldichloro
phosphite in MTBE with 2.2 equivalents of n-hexyl Grig-
nard at –78 °C, and warmed to ambient temperature. A
thick slurry due to the precipitation of MgCl2 ether com-
plex formed. Attempted standard filtration of this slurry
revealed that the intermediate phosphinite 4 (Scheme 2)
was not stable in air. We therefore developed a simple in-
line filtration to remove these salts while maintaining an
inert atmosphere. Vacuum transfer of the reaction slurry
through a commercial air-free filter we have previously
described3 into a second flask effectively removed the
salts. Toluene was then added to this solution and the
ethers removed by vacuum distillation. This furnished a
toluene solution of the phosphinite ready for DIBAL-H
reduction. Reduction was then carried out in one hour at
50 °C, and the synthesis completed by addition of 1.1
equivalents of BH3 and overnight aging at ambient tem-
perature. The overall isolated yield of target 6 from 3, af-
ter chromatography, was 67%.
Diisobutylaluminium hydride is one of the least expensive
reducing agents available due to its widespread applica-
tion in the polymer industry. We have recently reported
the use of DIBAL-H in efficient reductions of secondary
phosphine oxides1 and tertiary phosphine oxides,2 includ-
ing detailed experimental procedures for these new meth-
odologies.3 As part of a general program to expand the use
of DIBAL-H in organophosphorus chemistry, we chose to
first examine the reactivity of phosphinites. The reduction
of phosphinites to secondary phosphines has been previ-
ously reported with LAH and AlH3,4 though both of these
reagents pose significant problems for large-scale use.1,3
The reduction of phosphinite borane complexes have also
been described with lithium naphthalenide and related re-
ductants, though these reagents are not practical for scale-
up either.5
The 31P NMR experiments rapidly established that 2.2
equivalents of DIBAL-H would reduce commercial ethyl-
diphenylphosphinite quantitatively to diphenylphosphine
in one hour at 50 °C in C6D6. Addition of 1.1 equivalents
of BH3·SMe2 to this solution at ambient temperature led to
clean formation of the secondary phosphine borane, and
the product was obtained in high yield on gram scale, as
shown in Scheme 1.
There are several items of note associated with this sec-
ondary phosphine borane synthesis. The route is efficient,
with >90% average yield per step. In addition, no isolation
of air-sensitive intermediates 4 or 5 was made, and only
the stable borane complex was handled. Although we
OEt
DIBAL-H (1.2 equiv)
P
n-HexMgCl (2.2 equiv), MTBE
EtOPCl2
1 h, 50 °C, PhMe
–78 °C to 23 °C
3
4
–
BH3
H
H
P
P+
BH3 (1.1 equiv), 23 °C
67% from 3
5
6
Scheme 2
SYNLETT 2009, No. 2, pp 0287–0291
x
x.
x
x.
2
0
0
9
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087671; Art ID: S07808ST
© Georg Thieme Verlag Stuttgart · New York

288
C. A. Busacca et al.
LETTER
Cl
P
DIBAL-H (1.2 equiv)
–78 °C to r.t.
i-BuMgCl (1.1 equiv), MTBE
–78 °C to 23 °C
t-BuPCl2
10
PhMe
11
–
BH3
H
P
H
BH3 (1.1 equiv), 23 °C
P+
69% from 10
12
13 (mp 40–42 °C)
Scheme 3
–
Cl
BH3
H
DIBAL-H (1.1 equiv)
–78 °C to r.t.
PhMe, then BH3
P+
P
17
18 (89%)
Cl
–
H
BH3
P+
DIBAL-H (1.1 equiv)
–78 °C to r.t.
PhMe, then BH3
P
19
20 (85%)
Cl
P
H
P
DIBAL-H (1.1 equiv)
–78 °C to r.t.
C6D6
Ph
Ph
Ph
Ph
+
P
P
21
22
23
Scheme 4
found the sequence could be carried out in one pot without duction of the intermediate chlorophosphine was then ef-
removal of the magnesium salts, this led to a very difficult fected with 1.2 equivalents of reductant from –78 °C to
workup following quench with aqueous NaOH.1 This was room temperature, followed by in situ borane complex
caused by the presence of both Mg and Al salts in water. formation as before.6 A yield of 69% of the crystalline tar-
The Mg(II) salts are best solubilized by acid, while aque- get was achieved for the three-step sequence. Once again,
ous base is essential to the production of aluminum hy- no isolation of the air-sensitive intermediates was per-
droxide from the organoaluminum component.1,3 Since formed. The tert-butyl(cyclohexyl) analogue 14, was pre-
these two pH values are mutually exclusive, gel formation pared similarly (Table 1, entries 6 and 7).
occurred under basic conditions. In contrast, removal of
the Mg salts allows for a smooth quench and extraction
under basic conditions. We also observed that the
Entries 8 and 9 of Table 1 show secondary phosphine bo-
ranes 15 and 16 prepared from their respective dichloro-
phosphines. These mixed aryl/alkyl complexes could be
DIBAL-H charge could generally be reduced by one full
prepared with either order of nucleophile addition.
equivalent when the Mg salts were removed first. This in
To gain a deeper understanding of the scope of DIBAL-H
turn led to a faster quench and easier workup.
reductions of chlorophosphines, three commercial sub-
strates were examined (Scheme 4). The hindered di-tert-
butyl- and dicyclohexyl-chlorophosphines were cleanly
Table 1 (entries 2–5) shows the preparation of a series of
dialkyl secondary phosphine boranes (6–9) using the
same protocol described here. In the case of the more ster-
reduced to the desired secondary phosphines, and the
ically hindered dicyclohexyl target 9, 2.2 equivalents of
phosphine boranes were isolated in good overall yield.
DIBAL-H were required.
For the less hindered Ph2PCl, however, 31P NMR showed
We were interested in the preparation of unsymmetrical that the desired product was accompanied by a second
dialkylphosphine boranes as well, and explored their for- component. We ultimately determined that this byproduct
mation from commercial dichlorophosphines. Scheme 3 was the bisphosphine 23. Presumably, the secondary
shows the synthesis of the novel species tert-butyl(isobu- phosphine product reacted rapidly once formed with the
tyl)phosphine borane 13 from tert-BuPCl2 and i-BuMgCl. chlorophosphine starting material.7 We found that these
In-line filtration of MgCl2 was performed as described bisphosphine byproducts could also be reduced to the sec-
above, and the solvent was switched to toluene. The re- ondary phosphines by DIBAL-H. For the diaryl substrate,
Synlett 2009, No. 2, 287–291 © Thieme Stuttgart · New York

LETTER
Reduction of Phosphinites and Phosphinates
289
Table 1 Preparation of Secondary Phosphine Boranes
Entry
SMa
Product
Product
(equiv)b
Temp
(°C)c
Mp (°C)
Yield
31P NMR (C6D6),j
d (ppm)
(%)d–h
1
2
Ph2POEt
Ph2PH-BH3
2 (2.2)
50
50
50
50
50
23i
23i
23i
23i
23i
23i
50
50
50
75
90
46–47
– (oil)
– (waxy)
– (oil)
80–81
40–42
– (oil)
– (oil)
– (oil)
62–63
80–81
46–47
– (oil)
53–54
– (oil)
– (oil)
90d
67f
75f
30f
50f
69e
50e
60e
49e
97d
78d
84d
80d
63d
54d
40d
2.13
EtOPCl2
n-Hex2PH-BH3
i-Bu2PH-BH3
6 (1.2)
–7.04
–18.99
12.95
19.20
17.79
36.73
12.94
–8.08
49.15
19.20
2.13
3
EtOPCl2
7 (1.1)
4
EtOPCl2
t-Bu-MePH-BH3
c-Hex2PH-BH3
t-Bu-i-BuPH-BH3
t-Bu-c-HexPH-BH3
c-Hex-m-xylPH-BH3
Ph-i-BuPH-BH3
t-Bu2PH-BH3
8 (2.2)
5
EtOPCl2
9 (2.2)
6
t-BuPCl2
13 (1.1)
14 (1.1)
15 (1.2)
16 (1.1)
18 (1.1)
9 (1.1)
7
t-BuPCl2
8
c-HexPCl2
PhPCl2
9
10
11
12
13
14
15
16
t-Bu2PCl
c-Hex2PCl
Ph2PCl
c-Hex2PH-BH3
Ph2PH-BH3
2 (2.2)
PhMeP(O)(OMe)
Ph-2-NaphP(O)(OEt)
Ph-(m-xyl)P(O)(OEt)
Ph-NBNP(O)(OEt)k
PhMePH-BH3
26 (2.2)
27 (3.2)
28 (2.2)
29 (3.5)
–14.76
2.37
Ph-2-NaphPH-BH3
Ph-(m-xyl)-PH-BH3
2.07
k
Ph-NBN-PH-BH3
11.06, 7.83l
a Starting material.
b Equiv DIBAL-H.
c Reduction temp.
d Isolated yield over 2 steps.
e Isolated yield over 3 steps.
f Isolated yield over 4 steps.
g Distilled yield.
h Crude yield.
i –78 °C to r.t.
j Calibrated to 85% H3PO4 (0.0 ppm).
k NBN = norbornyl.
l Mixture of diastereomers; free secondary phosphines: d = –36.23, –38.12 ppm.
we thus added a Ph2PCl solution over two hours to 2.2 As depicted in Scheme 5, the phosphinate was cleanly re-
equivalents of DIBAL-H at 23 °C, and then aged one hour duced with 2.2 equivalents of DIBAL-H at 50 °C for two
at 50 °C, furnishing the diarylphosphine cleanly. Gram- hours in C6D6. In situ borane complex formation was
scale reductions of all three chlorides could thus be effi- again achieved with 1.1 equivalents of BH3·SMe2 at am-
ciently performed, as shown in entries 10–12 of Table 1.
bient temperature. When the reaction was then performed
on gram scale in toluene, 80% isolated yield of phenyl-
methylphosphine borane 26 was achieved following chro-
matographic purification (Table 1, entry 13). Two
unsymmetrical diarylphosphinates were prepared by the
known method,10c and similarly reduced to furnish novel
diaryl phosphine boranes 27 and 28 in good overall yield
(entries 14 and 15). Hydrophosphination of norbornene,
followed by reduction and complex formation produced
novel phenyl-norbornylphosphine borane 29 in similar
fashion (entry 16).
Phosphinates are species readily produced by a number of
synthetic methods including the Michaelis–Arbuzov reac-
tion between phosphonites and alkyl halides,8 radical
hydrophosphination of olefins,9 transition-metal-cata-
lyzed cross-couplings,10 and alkylation.11 We began our
research with commercial phenylmethyl methylphosphi-
nate (24). As with all new substrate classes, we first exam-
ined reactivity with 31P NMR, running reactions in
septum-capped NMR tubes.12 In this way we were able to
quickly establish key reaction parameters such as reduc-
tant stoichiometry, temperature, optimum solvent, and re- In summary, the unique reducing abilities of DIBAL-H
action time before any ‘true’ reactions in flasks were towards organophosphorus species have been successful-
performed.
ly extended to include phosphinites, phosphinates, and
Synlett 2009, No. 2, 287–291 © Thieme Stuttgart · New York

290
C. A. Busacca et al.
LETTER
–
BH3
H
P
H
O
OMe
Me
P+
P
DIBAL-H (2.2 equiv),
50 °C, 2 h
Me
Me
BH3 (1.1 equiv)
25
24
26 (80%)
–
–
BH3
BH3
H
–
H
H
BH3
P+
P+
P+
Me
27 (63%)
28 (54%)
29 (40%)
Me
Scheme 5
funnel and the phases separated. All organics were combined,
washed with half-saturated NaCl (1 × 100 mL), dried (MgSO4), and
concentrated on the rotary evaporator to ca. 15 mL final volume (do
NOT concentrate to dryness2). This solution was then filtered in 5
min through a short silica gel column, eluting with MTBE (150
mL). The eluent was stripped in vacuo to give a colorless oil. The
oil was then chromatographed on SiO2 eluting with hexane–EtOAc
(20:1) and staining with KMnO4 to give, after drying under high
vacuum, 7.21 g of 6 (67% over 4 steps) as a colorless oil.
chlorophosphines. Efficient and economical procedures
to access secondary phosphine boranes have been devel-
oped that avoid isolation of all air-sensitive intermediates,
giving these important targets in good overall yield.
General Procedure A: Synthesis of Secondary Phosphine Bo-
ranes from EtOPCl2 (6)
A four-neck 500 mL flask was equipped with a mechanical stirrer,
an addition funnel, a Claisen adapter with thermocouple and inert
gas valve, and a Teflon transfer line to an air-free filter atop a sec-
ond 500 mL flask. To the inerted reactor was then charged in suc-
cession through the addition funnel MTBE (50 mL), EtOPCl2 (5.71
mL, 50 mmol, 1.0 equiv), and THF (50 mL). The solution was
cooled in a –78 °C bath, then 2 M n-hexMgBr in Et2O (55 mL, 110
mmol, 2.2 equiv) was charged to the addition funnel. At –65 °C, the
Grignard was added dropwise over 30 min, then aged 30 min at ca.
–78 °C. The slurry was then allowed to warm to 23 °C.
General Procedure B: Synthesis of Secondary Phosphine Bo-
ranes from Phosphinates (27)
Part 1. A three-neck 500 mL flask was charged with PdCl2(dppf)
(1.013 g, 1.24 mmol, 0.03 equiv), 2-bromonaphthalene (8.28 g, 40.0
mmol, 1 equiv), and ethylphenylphosphinate (6.03 mL, 40.0 mmol,
1 equiv). The flask was evacuated/Ar filled (3×), then MeCN (160
mL) and Et3N (11.19 mL, 80.0 mmol, 2 equiv) were added via sy-
ringe in the order given. The resulting mixture was then placed in a
pre-equilibrated 65 °C oil bath under Ar. After 16 h, the mixture
was cooled to ambient temperature, diluted with EtOAc (200 mL),
and then filtered to remove Et3N·HBr. The filtrate was concentrated
in vacuo, and the residue chromatographed on SiO2 eluting with
hexane–EtOAc (1:1) to give, after drying under high vacuum, 9.40
g of the phenyl-2-naphthyl phosphinate (79%) as a viscous, yellow
oil. 31P NMR (202 MHz, C6D6): d = 29.38 ppm.
After 1.5 hours at 23 °C, MTBE (50 mL) was added, stirred 10 min,
then vacuum was applied to the second flask, drawing the slurry
through the airfree filter. The first reactor was then washed with
MTBE (2 × 40 mL) to transfer the last of the slurry. The second re-
actor was then isolated from the first reactor. A clean, dry 1 L 4-
neck flask was then installed with mechanical stirrer, short-path dis-
tillation head to a receiver flask, addition funnel, and thermocouple.
The filtrate in the second reactor was then transferred via cannula
under N2 pressure to the 1 L flask, and then PhMe (50 mL) was add-
ed as a wash of the second reactor and transferred via cannula as be-
fore. The 1 L flask was then configured for house vacuum (ca. 0.11
bar) distillation by freezing the receiver (–78 °C) and flowing water
through the still head. The temperature was raised in steps to 45 °C,
collecting all the ethers in the receiver and leaving a toluene solu-
tion of the phosphinite in the reactor.
Part 2. A three-neck 100 mL flask with an addition funnel was
charged with the phenyl-2-naphthyl phosphinate (2.4 g, 8.1 mmol,
1 equiv) described above, then evacuated/Ar filled (2×), then PhMe
(15 mL) was added via syringe. 1.5 M DIBAL-H in PhMe (17.8 mL,
26.7 mmol, 3.3 equiv) was then added via addition funnel over ca.
5 min, causing an orange mixture to form. The flask was then placed
in a pre-equilibrated 50 °C oil bath under Ar. After 6 h, an aliquot
was transferred to a screw-cap NMR tube containing C6D6. To this
NMR tube was then cautiously added N,N-dimethylaminoethanol
(ca. 0.1 mL) as a quench. 31P NMR showed nearly pure secondary
phosphine at d = –27 ppm. 10 M BH3·SMe2 (1.2 mL, 12 mmol, 1.5
equiv) was then added at once to the reactor via syringe, and the
mixture allowed to stir overnight at r.t.
Vacuum was switched to argon and the flask cooled to 23 °C. To the
phosphinite solution was then added 1.5 M DIBAL-H in PhMe (40
mL, 60 mmol, 1.2 equiv) via addition funnel over 3 min causing an
exotherm to 51 °C. The batch was then heated at 50 °C for 2 h, then
cooled to 23 °C. 10 M BH3·SMe2 (6.0 mL, 60 mmol) was then add-
ed at once via syringe. The batch was then stirred overnight at am-
bient temperature.
The reaction mixture was cooled to –78 °C, then 4 N NaOH (14
mL) was added cautiously via the addition funnel. The cold bath
was then removed and the mixture allowed to warm to r.t., and
stirred 1 h at r.t. The mixture was then poured into a separatory fun-
nel, giving a clear organic phase on top of an aqueous suspension.
The upper organic phase was separated and saved, while the lower
aqeuous phase was filtered through a Celite pad, washing the pad
with PhMe (2 × 20 mL). All organics were combined, washed with
half-saturated NaCl (2 × 25 mL), and then dried over MgSO4. The
PhMe solution was then concentrated on the rotary evaporator to ca.
20 mL (do NOT concentrate to dryness2), then filtered by gravity
through a short column of SiO2 in a fritted funnel, eluting with ad-
The mixture was cooled in a –78 °C bath, then quenched by the
dropwise addition of 4 N NaOH (45 mL) over 15 min, then warmed
to 23 °C. After 1 h at ambient temperature, the mixture was poured
into a separatory funnel and allowed to settle, giving a PhMe solu-
tion above an aqueous suspension. The aqueous phase was filtered
through a Celite pad while agitating with a spatula, and the organic
phase was separated and saved. The Celite pad was washed with
PhMe (2 × 40 mL) and the filtrate was transferred to a separatory
Synlett 2009, No. 2, 287–291 © Thieme Stuttgart · New York

LETTER
Reduction of Phosphinites and Phosphinates
291
ditional PhMe (ca. 50 mL). The eluents were then concentrated in
vacuo to give a yellow oil which was azeotroped with heptane on
the rotary evaporator and finally dried under high vacuum on the ro-
tary evaporator to give 1.25 g of pure 27 (63%) as a colorless oil
which crystallized on standing; mp 53–54 °C.
(5) (a) Stankevic, M.; Pietrusiewicz, K. M. J. Org. Chem. 2007,
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(d) Imamoto, T.; Matsuo, M.; Nonomura, T.; Kishikawa, K.;
Yanagawa, M. Heteroat. Chem. 1993, 4, 475.
(6) For the reduction of chlorophosphine–borane complexes
with a variety of reducing agents, see: (a) Lam, H.; Aldous,
D. J.; Hii, K. K. Tetrahedron Lett. 2003, 44, 5213.
(7) (a) Dodds, D. L.; Haddow, M. F.; Orpen, A. G.; Pringle,
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(8) For reviews, see: (a) Engel, R.; Cohen, J. L. I. Synthesis of
Carbon–Phosphorus Bonds; CRC Press: Boca Raton, 1988,
Chap. 3 and 6. (b) Bhattacharya, A. K.; Thyagarajan, G.
Chem. Rev. 1981, 81, 415.
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