Improved synthetic routes to methylene-bridged P-chiral diphosphine ligands via secondary phosphine-boranes

Article abstract of DOI:10.1016/j.tetasy.2010.03.025

Improved methods for the preparation of methylene-bridged diphosphine ligands are described. Both enantiomers of the key intermediate tert-butylmethylphosphine-borane were prepared via resolution or by the conversion of one enantiomer into the opposite en

Full text of DOI:10.1016/j.tetasy.2010.03.025

Tetrahedron: Asymmetry 21 (2010) 1522–1528
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Improved synthetic routes to methylene-bridged P-chiral diphosphine
ligands via secondary phosphine–boranes
Tsuneo Imamoto a,b, , Ken Tamura a,b, Tomokazu Ogura b, Yui Ikematsu b, Daisuke Mayama a,
*
Masashi Sugiya a
a Organic R&D Department, Nippon Chemical Industrial Co., Ltd, Kameido, Koto-ku, Tokyo 136-8515, Japan
b Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Improved methods for the preparation of methylene-bridged diphosphine ligands are described. Both
enantiomers of the key intermediate tert-butylmethylphosphine–borane were prepared via resolution or
by the conversion of one enantiomer into the opposite enantiomer. The precursor borane complexes of bis
(tert-butylmethylphosphino)methane (t-Bu-MiniPHOS), bis((1,1,3,3-tetramethylbutyl)methylphosphi-
no)methane (t-Oct-MiniPHOS), and (tert-butylmethylphosphino)(di-tert-butylphosphino)methane (trich-
ickenfootphos) were prepared in good yields and enantiopure form.
Received 3 March 2010
Accepted 26 March 2010
Available online 11 May 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
(13–28%). Another problem of this method is that it uses (ꢀ)-spar-
teine as the chiral source which only gives the (R,R)-enantiomer li-
Among the numerous chiral phosphine ligands reported so far,1
P-stereogenic bis(alkylmethylphosphino)methanes (MiniPHOS)
are known to have unique stereochemical properties. They are a
class of electron-rich diphosphines and their low-valent transi-
tion-metal complexes are more susceptible to oxidative addition
than the corresponding complexes that have ligands possessing
diarylphosphino groups. In addition, they are methylene-bridged
diphosphines and would form rigid four-membered metal
complexes. In fact, we have previously synthesized four-
membered chelates by reaction with [Rh(nbd)2]X (X = BF4, PF6).2
Among the several known MiniPHOS ligands, (R,R)-bis(tert-butyl-
methylphosphino)methane ((R,R)-t-Bu-MiniPHOS) has proven to
be the most useful chiral ligand not only in the Rh-catalyzed asym-
metric hydrogenation2,3 but also in other asymmetric catalyses,
such as the hydrosilylation of simple ketones,2a,4 the conjugate
gands, and the opposite enantiomer (S,S)-ligands cannot be
synthesized by the same methodology because of the practical
unavailability of (+)-sparteine.7 These drawbacks in the synthesis
have hampered their widespread application in asymmetric catal-
yses and thus, it is strongly desired that an efficient method for the
synthesis of this class of chiral ligands, including both enantiomers,
be developed.
BH3
P
BH3
P
(—)-sparteine/s-BuLi
R
R
CH2Li
Me
Me
Me
R = t-Bu, 1-Ad, c-C6H6, i-Pr, Ph
addition of dialkylzinc reagents to
a
,b-enones,2a,5 and the ring-
BH3 BH3
BH3 BH3
1. RPCl2
opening reaction of azabenzonorbornadienes.6
+
P
P
P
P
R
Me
R
R
2. MeMgX
Me
R
Me
Me
Me
R
R
3. BH3•THF
chiral
P
P
meso
Me
MiniPHOS
1. TfOH
or HBF4
BH3 BH3
recrystallization
13—28%
Me
R
R
The ligand (R,R)-t-Bu-MiniPHOS and its analogues can be pre-
pared from alkyl(dimethyl)phosphine–borane via a short synthetic
route (Scheme 1).2 This method, however, involves the formation
of considerable amounts of meso compounds and eventually
affords the desired enantiopure MiniPHOS precursors in low yields
P
P
P
P
R
Me
2. KOH
Me
Me
R
MiniPHOS
enantiopure
Scheme 1. Previously reported synthetic route to MiniPHOS ligands.
Recently, O’Brien et al. reported a synthetic route from tert-
butyldimethylphosphine sulfide to (S,S)-t-Bu-MiniPHOS.8 Their
* Corresponding author. Tel./fax: +81 043 290 2791.
E-mail address: imamoto@faculty.chiba-u.jp (T. Imamoto).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.025

T. Imamoto et al. / Tetrahedron: Asymmetry 21 (2010) 1522–1528
1523
method uses (ꢀ)-sparteine as the chiral source and involves (S)-
tert-butyl(methyl)(trimethylsilylmethyl)phosphine sulfide as the
key intermediate; the protocol is also applicable to the synthesis
of analogous P-chiral phosphine ligands. On the other hand,
2.2. Preparation of both enantiomers of tert-butylmethylphos-
phine–borane
Our main aim in this study was to establish a procedure for the
large-scale preparation of both enantiomers of t-Bu-MiniPHOS. Our
first approach was to employ resolution.14 In this regard, tert-
butylphosphine–borane 6 was methylated and the resulting race-
mic compound 3 was converted into a mixture of diastereomers
7 with a bornyl group. Fractional recrystallization of 7 provided
(R)-7 with 95% de and (S)-7 with 52% de. Compound (R)-7 was
hydrolyzed to give (S)-3 without any decease in enantiomeric pur-
ity and (S)-3 was further converted into (R)-2 upon treatment with
paraformaldehyde in the presence of NaH in THF (Scheme 3). This
approach was effective for the preparation of one enantiomer (S)-3,
but was not suitable for the preparation of enantiomer (R)-3 with
high ee.
Jackson and Lennon prepared
a methylene-bridged analogue
(R,R)-1,2-bis(2,5-diphenylphospholano)methane from a secondary
phosphine–borane (R,R)-2,5-diphenylphospholane–borane.9
We attempted to develop efficient procedures for the synthesis
of both enantiomers of t-Bu-MiniPHOS and related compounds.
Herein, we report our synthetic approach to these compounds
together with the preparation of a precursor of (S)-(tert-butyl-
methylphosphino)(di-tert-butylphosphino)methane (trichicken-
footphos)10 which was developed by Hoge and co-workers.
2. Results and discussion
An alternative route is shown in Scheme 4. Racemic secondary
phosphine–borane 3 was reacted with (S)-a-methylbenzylisocya-
2.1. Preparation of the precursor of (R,R)-bis(tert-
butylmethylphosphino)methane [(R,R)-t-Bu-MiniPHOS]
nate to give a mixture of two diastereomers (S)-8 and (R)-8. Recrys-
tallization from a mixed solvent of hexane and ethyl acetate
afforded one diastereomer (S)-8 with 97% de in 37% yield. Subse-
quent removal of the chiral auxiliary by treatment with KOH in
MeOH/DMF led to (R)-3 in 73% yield. The ee of this product was
found to be 86% to indicate that partial racemization had occurred
under the reaction conditions.
In our previous study, optically active tert-butyl(hydroxy-
methyl)methylphosphine–borane 2 was obtained in good yield
by the enantioselective deprotonation of tert-butyl(dimethyl)phos-
phine–borane 1 with the (ꢀ)-sparteine/s-BuLi reagent, followed by
the oxidation with molecular oxygen.11 We found also that
compound (R)-2 was subjected to stereospecific, oxidative one-
carbon degradation on treatment with K2S2O8 in the presence of
RuCl3 as a catalyst to afford secondary phosphine–borane (S)-3 in
high yield.11 It was also observed that the phosphido anions de-
rived from chiral secondary phosphine–boranes exhibited strong
nucleophilicity during substitution reaction with alkyl halides
while keeping the stereochemical integrity at the P-stereogenic
center.12 Based on these facts, we envisioned that the reaction of
compound (S)-3 with a sulfonate derivative of compound (R)-2
would yield the precursor of (R,R)-t-Bu-MiniPHOS (Scheme 2).
In order to realize this idea, compound (R)-2 with 92% ee was
converted into its benzoyl derivative, and this derivative was
recrystallized from hexane/ethyl acetate (20:1).13 The resulting
enantiopure compound was returned to (R)-2 by hydrolysis and
this was converted into (S)-3 and (R)-4. Compound (S)-3 was trea-
ted with n-BuLi and the subsequent reaction with (R)-4 afforded
MiniPHOS precursor (R,R)-5 in 62% yield.
It should be noted that the two methods mentioned above can
be employed for the large-scale preparation of both enantiomers
(S)-3 and (R)-3. These enantiomers can be used for the production
of not only MiniPHOS ligands but also other P-chiral phosphine
ligands. In fact, they have been used for the kilogram-scale produc-
tion of both enantiomers of 2,3-bis(tert-butylmethylphosphino)-
15
*
quinoxaline (QuinoxP ).
2.3. Conversion of (S)-tert-butylmethylphosphine–borane into
the opposite enantiomer
Previously, we studied nucleophilic substitution reactions
occurring at the P-stereogenic center, using in situ generated (R)-
bromo(tert-butyl)methylphosphine–borane.16 A notable fact found
in that study is that alkynyllithium reagents reacted smoothly to
give the substitution products in high yields and almost exclu-
sively with inversion of configuration. The results led us to envis-
age that the use of hydride reagents, such as LiAlH4, would give
the inversion product, and hence this reaction would become an
interconversion process between one enantiomer of a secondary
phosphine–borane and its opposite isomer.
One of the features of this method is that the desired compound
was obtained in good yield without the formation of a meso-iso-
mer. Another feature is that the two chiral components (S)-3 and
(R)-4 were prepared from the same intermediate (R)-2. These re-
sults suggest that similar diphosphine ligands, including unsym-
metric ones, can be prepared by this methodology.
1. (—)-sparteine/s-BuLi
K2S2O8
BH3
P
BH3
P
BH3
2. O2
RuCl3 (5 mol%)
P
t-Bu
Me
t-Bu
Me
t-Bu
Me
CH2OH
H
Me
85%
78%
1
(S)-3
(R)-2
92% ee
>99% ee
BzCl,pyridine
recry. from hexane/AcOEt (20:1)
then KOH/Aq. EtOH
n-BuLi
TsCl, Et3N
82%
BH3
P
t-Bu
Me
Li
BH3
P
BH3 BH3
P
P
t-Bu
Me
t-Bu
Me
Me
Bu-t
CH2OTs
62%
(R)-4
(R,R)-5
Scheme 2. Preparation of the precursor of t-Bu-MiniPHOS.

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T. Imamoto et al. / Tetrahedron: Asymmetry 21 (2010) 1522–1528
1. n-BuLi, THF
1. n-BuLi
2. CH3I
BH3
P
BH3
2. (—)-bornyl chloroformate
BH3
P
t-Bu
t-Bu
P
O
H
H
t-Bu
Me
H
Me
O
3
6
dl-form
7
mixture of two
diastereomers
KOH
H2O
BH3
BH3
P
BH3
P
(CH2O)n/NaH
THF, 0 °C ~ rt
P
OR*
t-Bu
Me
t-Bu
Me
t-Bu
Me
CH2OH
H
fractional
recrystallization
O
95% de
(R)-2
95% ee
(R)-7
(S)-3
R* = (—)-bornyl
OR*
95% ee
BH3
P
Me
t-Bu
O
(S)-7
52% de
Scheme 3. Preparation of compounds (S)-3 and (R)-2 via resolution.
2.4. Preparation of borane complex of (S)-(tert-butylmethyl-
phosphino)(di-tert-butylphosphino)methane
BH3
H
BH3
P
KOH (20 mol%)
MeOH/DMF
P
N
Ph
Me
t-Bu
Me
t-Bu
H
OCN
Me
Ph
Me
H
O
Different from many chiral C2-symmetric diphosphine ligands,
(S)-(tert-butylmethylphosphino)(di-tert-butylphosphino)methane
(trichickenfootphos) is unique, because it is C1-symmetric and its
four-membered rhodium complex forms three hindered quad-
rants. Most notable is that the rhodium complex exhibits extre-
mely high catalytic activity and almost perfect enantioselectivity
in the asymmetric hydrogenation of dehydroamino acids and re-
lated compounds.10 Therefore, these features make the asymmetric
hydrogenation reaction a potentially useful tool for the industrial
production of a pharmaceutically important chiral compound.
This ligand was previously prepared via chiral preparative
HPLC.10a We attempted to prepare this important chiral ligand
from optically active tert-butylmethylphosphine–borane with a
view to large-scale production. Our initial trial was conducted with
(R)-3 (86% ee) prepared by the method shown in Scheme 4.
The reaction pathway to the precursor of trichickenfootphos is
shown in Scheme 6. Compound (R)-3 was converted into (S)-2
and after increasing the ee to >99%, it was reacted successively
with n-BuLi and trifluoromethanesulfonic anhydride to generate
triflate 10. Subsequent reaction with the lithio derivative of di-
tert-butylphosphine–borane provided 11 in a synthetically accept-
able yield. It is worthy of note that the isolated tosylate or mesylate
of compound (S)-2 reacted sluggishly with the bulky nucleophile to
give 11 in very low yields. Attempts to isolate triflate intermediate
10 in the pure form were unsuccessful because it was unstable and
decomposed during chromatography on silica gel.
(R)-3
86% ee
BH3
P
(S)-8
H
97% de
t-Bu
H
Me
BH3
3
H
N
P
Ph
t-Bu
Me
Me
H
O
(R)-8
Scheme 4. Preparation of (R)-tert-butylmethylphosphine–borane via resolution.
The transformation was simple: secondary phosphine–borane
(S)-3 with >99% ee was reacted successively with n-BuLi and 1,2-
dibromoethane to generate intermediate 9 at ꢀ80 °C through
ꢀ40 °C. The addition of LiAlH4 to the mixture, followed by warming
to 0 °C, afforded the counter enantiomer (R)-3 with 97% ee in 90%
yield (Scheme 5). In this transformation, the solvent choice was
important; the use of THF in place of diethyl ether resulted in very
low product yields. Replacing the hydride reagent LiAlH4 with
NaBH4 resulted in no trace of the desired compound.
1. n-BuLi
This procedure employing the in situ generation of 10 yielded
many by-products; nevertheless, compound 11 was crystallized
from the reaction mixture. Overall, this process utilizes no chroma-
tography and hence is suitable for large-scale production.
BH3
P
BH3
P
2. Br(CH2)2Br
t-Bu
Me
t-Bu
Me
H
Br
Et2O
(S)-3>99% ee
9
2.5. Preparation of (R,R)-bis(methyl(1,1,3,3-tetramethylbutyl)
phosphino)methane [(R,R)-t-Oct-MiniPHOS]
BH3
P
LiAlH4
90%
Me
t-Bu
H
Based on the experimental results mentioned above, we tried to
prepare a new MiniPHOS ligand possessing tert-octyl groups.
Scheme 7 shows the transformation from starting phosphine–bor-
ane 12 to target compound 18 and its rhodium complex 19. The
conversion of 12 into (R)-13 was carried out in the usual manner,
(R)-3
97% ee
Scheme 5. Conversion of (S)-tert-butylmethylphosphine–borane to the opposite
enantiomer.

T. Imamoto et al. / Tetrahedron: Asymmetry 21 (2010) 1522–1528
1. n-BuLi
1525
BH3
BH3
P
BH3
P
2. Tf2O
(CH2O)n/NaH
P
Me
t-Bu
Me
t-Bu
(R)-3
Me
t-Bu
CH2OTf
10
H
CH2OH
Et2O
THF, 0 °C ~ rt
(S)-2
86% ee
86% ee
BzCl, triethylamine
recry. from hexane/AcOEt (20:1)
then KOH/aq. EtOH
>99% ee
BH3 BH3
t-Bu2P(BH3)Li
THF
Me
DABCO
P
P
P
P
Me
Bu-t
Bu-t
t-Bu
11
Trichickenfootphos
Scheme 6. Preparation of borane adduct of (S)-(tert-butylmethylphosphino)(di-tert-butylphosphino)methane.
1. (—)-sparteine/
s-BuLi
2. O2
1. NaH
2. RSO2Cl
BH3
P
BH3
P
BH3
P
t-Oct
Me
CH2OH
t-Oct
Me
Me
CH2OSO2R
Me
(R)-13
12
(R)-14a: R = 4-MeC6H4
(R)-14b: R = Me
92% ee
p-ClC6H4COCl, pyridine
recry. from hexane
>99% ee
then KOH/Aq. EtOH
RuCl3 (5 mol%)
K2S2O8, KOH
Me
t-Oct
Me
1. TfOH
2. KOH
P
P
P
Rh+
BH3
BH3
BH3 BH3
(R)-14b
[Rh(nbd)2]BF4
n-BuLi
Oct-t
Me
t-Oct
Me
–
P
P
BF4
P
Li
P
P
P
H
t-Oct
t-Oct
Me
Me
Oct-t
t-Oct
Oct-t
Me
t-Oct
Me
Me
Me
P
Oct-t
(S)-15
16
17
18
19
Scheme 7. Synthesis of (R,R)-t-Oct-MiniPHOS and its rhodium complex.
but without the addition of triethylphosphite.11 To increase the ee
of the resulting compound, its benzoyl derivative was prepared but
the product was a pasty oil and did not crystallize. Therefore, we
prepared the p-chlorobenzoyl derivative. Recrystallization of the
derivative from hexane increased the ee from 92% to >99%, and this
derivative was converted into (R)-13 by hydrolysis. This compound
was transformed into tosyl and mesyl derivatives (R)-14a and (R)-
14b and secondary phosphine–borane (S)-15. The coupling reac-
tion of lithio derivative 16 with tosyl derivative (R)-14a resulted
in only a trace amount of 17, probably because of the steric hin-
drance by the bulky tosyl group. In contrast, use of the mesyl deriv-
ative provided the product, although the yield was moderate.
Compound 17 was subjected to borane deprotection to give de-
sired (R,R)-t-Oct-MiniPHOS 18. As this ligand was sensitive upon
exposure to air, it was immediately converted into rhodium com-
plex 19. The enantioinduction ability of this complex was tested
by probing of the Rh-catalyzed asymmetric hydrogenation of
tert-butylmethylphosphine–borane could be synthesized on a
large-scale and hence this methodology is applicable to the indus-
trial production of t-Bu-MiniPHOS and related compounds.
4. Experimental
4.1. General methods
All anaerobic and moisture-sensitive manipulations were car-
ried out with standard Schlenk techniques under predried nitrogen
or glove box techniques under prepurified argon. NMR spectra
were recorded on a JEOL JNM LA-500 spectrometer (500.00 MHz
for 1H, 125.65 MHz for 13C, and 202.35 MHz for 31P). Chemical
shifts are reported in d ppm referenced to an internal standard [tet-
ramethylsilane for 1H NMR, chloroform-d (d 77.0) for 13C NMR, and
phosphoric acid for 31P NMR]. Mass spectra were recorded on a
JEOL JMS-HX110 and a JEOL LC-AccuTOF. Melting points were
determined with a YANACO Micro Melting Point Apparatus. HPLC
analysis was performed using a Shimadzu LC-10AD VP pump, an
SPD-10A VP UV detector, and a Shimadzu CTO-10AC VP column
oven. Anhydrous THF, Et2O, and tert-butyl methyl ether (MTBE)
were purchased from Kanto Chemical and used as received.
methyl (Z)-a-acetamidocinnamate (s/c = 100) in methanol under
2 atm of hydrogen pressure for 12 h to give 99.4% ee of the hydro-
genation product in quantitative yield.
3. Conclusion
Improved synthetic routes to P-chiral methylene-bridged
diphosphine ligands are presented. These procedures involve the
nucleophilic reactions of the secondary phosphine–boranes with
sulfonate derivatives to give the desired compounds without the
formation of meso-isomers. Both enantiomers of key intermediate
4.2. Preparation of precursor of (R,R)-bis(tert-butylmethyl-
phosphino)methane ((R,R)-t-Bu-MiniPHOS) (R,R)-5
To a solution of (S)-3 (302 mg, 256 mmol) in THF (8 mL) was
added n-BuLi (1.73 mL of 1.55 M/L hexane solution, 2.68 mmol)

1526
T. Imamoto et al. / Tetrahedron: Asymmetry 21 (2010) 1522–1528
with stirring at 0 °C under argon. After 15 min, tosyl derivative (R)-
4 (775 mg, 2.56 mmol) was added and the mixture was stirred at
60 °C for 2 h. The reaction was quenched with 1 M HCl and the
mixture was extracted with ethyl acetate three times. The com-
bined extracts were washed with saturated NaHCO3 solution and
brine, and dried over Na2SO4. The solvent was evaporated under
reduced pressure and the residual solid was recrystallized from
methanol to afford (R,R)-5 (394 mg, 62%). The spectral data of this
product were consistent with those of the authentic sample.
to ꢀ40 °C and maintained for an additional 1 h. After the complete
consumption of the starting material as monitored by thin layer
chromatography on silica gel (hexane/ethyl acetate = 10:3), LiAlH4
(340 mg, 10 mmol) was added portionwise to the mixture and the
temperature was gradually elevated to 0 °C. The reaction mixture
was carefully transferred into saturated aq NH4Cl solution. The or-
ganic layer was separated and the aqueous layer was extracted
with diethyl ether three times. The combined extracts were
washed with brine and dried over MgSO4. The solvent was re-
moved at 25–30 °C under reduced pressure (17 mmHg) to give
(R)-tert-butylmethylphosphine–borane (R)-3 (530 mg, 90%, 97%
ee).17
4.3. (SP,S)-tert-Butyl(methyl)(1-phenylethylcarbamoyl)
phosphine–borane (S)-8
An oven-dried, four-necked, 4-L, round-bottomed flask was
equipped with a mechanical stirrer, a nitrogen inlet, a pressure-
equalizing dropping funnel, and a thermometer. The flask was
flushed with nitrogen and charged with racemic tert-butylmethyl-
phosphine–borane (141.8 g, 1.202 mol) and THF (600 mL). The
resulting solution was cooled in an ice bath and n-BuLi (75 mL of
1.59 M/L hexane solution, 0.12 mol) was added dropwise while
keeping the temperature below 10 °C. To the solution was slowly
4.6. Preparation of the precursor of (S)-(tert-butylmethyl-
phosphino)(di-tert-butylphosphino)methane
(trichickenfootphos)
To
a solution of (S)-tert-butyl(hydroxymethyl)methylphos-
phine–borane (1.76 g, 6 mmol) in diethyl ether (12 mL) was slowly
added n-BuLi (4.0 mL of 1.5 M/L hexane solution, 6.0 mmol) cooled
to ꢀ80 °C under argon. After 15 min, trifluoromethanesulfonic
anhydride (1.00 mL, 6 mmol) was added to the milky suspension
via a syringe over 15 min with vigorous stirring. The temperature
was gradually increased to ꢀ40 °C and to the mixture was added
a solution of the lithium derivative of di-tert-butylphosphine–bor-
ane prepared by the metalation of the secondary phosphine–bor-
ane (0.97 g, 6 mmol) in THF (12 mL) with n-BuLi (4.0 mL of
1.5 M/L hexane solution, 6.0 mmol) at 0 °C under argon. The mix-
ture was gradually warmed to room temperature, and then water
and ethyl acetate were added. The organic layer was separated
and the aqueous layer was extracted with ethyl acetate. The com-
bined extracts were washed with brine and dried over Na2SO4. The
solvent was removed under reduced pressure at a temperature be-
low 30 °C. The residual pasty oil was triturated with hexane to
form a crystalline solid, which was collected by filtration and
washed with hexane. Yield: 0.98 g, 56%. Further purification by dis-
solving the product in the minimum amount of ethyl acetate at
room temperature and diluting with hexane afforded colorless
crystals.
added (S)-a-methylbenzylisocyanate (176.8 g, 1.201 mol), and stir-
ring was continued for 12 h at room temperature. The reaction was
quenched by adding 5% HCl (90 g) and the mixture was well stirred
with hexane (240 mL) and water (240 mL). The organic layer was
separated, washed with 2.5% NaHCO3 solution and water, and
evaporated under reduced pressure. The residual solid was recrys-
tallized from a mixed solvent of ethyl acetate (240 mL) and hexane
(1800 mL) to give a white powder (118.6 g, 0.447 mol, 37%). The
diastereomeric excess of this product was determined to be 97%
by 1H NMR analysis. Mp 114–116 °C; ½a 2D5
¼ ꢀ46:7 (c 1.0, CHCl3);
ꢁ
1H NMR (CDCl3) d 0.5–1.0 (br q, 3H), 1.14 (d, J = 14.7 Hz, 9H),
1.45 (d, J = 10.5 Hz, 3H), 1.53 (d, J = 6.9 Hz, 3H), 5.15 (dt,
J = 6.9 Hz, 1H), 7.2–7.4 (m, 5H); 13C NMR (CDCl3) d 3.4 (d), 21.7,
25.3, 28.6 (d), 49.6 (d), 126.0, 127.6, 128.8, 142.2, 167.5 (d); 31P
NMR (CDCl3) d 33.6 (s). HRMS (TOF): calcd for C14H22NNaOP
(MꢀBH3+Na+): 274.1337; found: 274.1342.
4.4. Preparation of (R)-tert-butylmethylphosphine–borane (R)-
3 from (SP,S)-tert-butyl(methyl)((1-phenylethyl)carbamoyl)
phosphine–borane (S)-8
4.7. (R)-Hydroxymethyl(methyl)(1,1,3,3-tetramethylbutyl)
phosphine–borane (R)-13
A
solution of (SP,S)-tert-butyl(methyl)(1-phenylethylcarba-
moyl)phosphine–borane (7.97 g, 30.1 mmol) in DMF (30 mL) was
cooled in an ice bath, and to this solution was added 10% KOH
methanol solution (3.4 g, 6.0 mmol, 0.2 equiv). The ice bath was re-
moved and stirring was continued at room temperature for 12 h.
The flask was again immersed in an ice bath and hexane (30 mL),
water (60 mL), and 5% HCl (3.8 g, 6.0 mmol) were added succes-
sively. The organic layer was separated and the aqueous layer
was extracted with hexane five times. The combined extracts were
washed with brine, dried over Na2SO4, and evaporated under re-
duced pressure (17 mmHg) at 25–30 °C. The residue was purified
by column chromatography on silica gel using hexane/tert-butyl
methyl ether (100:3) as the eluent to give (R)-tert-butylmethyl-
phosphine–borane (2.57 g, 73%, 86% ee17).
To a stirred and cooled (ꢀ78 °C) solution of (ꢀ)-sparteine
(7.6 mL, 33 mmol) in Et2O (30 mL) was added s-BuLi (33 mL of
1.0 M solution in cyclohexane and n-hexane solution, 33 mmol)
under nitrogen atmosphere. After 30 min,
a solution of di-
methyl(1,1,3,3-tetramethylbutyl)phosphine–borane 1218 (5.64 g,
30 mmol) in Et2O (30 mL) was added dropwise and the reaction
mixture was stirred at the same temperature for 3 h and then grad-
ually warmed to ꢀ40 °C. After 1 h, oxygen gas was blown through
the solution with vigorous stirring and stirring was continued for
an additional 1 h. Then, the reaction solution was stirred at 0 °C
for 1 h and warmed at ambient temperature. After 1 h, the reaction
was quenched by the addition of 1 M HCl. The mixture was ex-
tracted with EtOAc, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The crude material was
purified by silica gel column chromatography (CH2Cl2) to give
(R)-hydroxymethyl(methyl)(1,1,3,3-tetramethylbutyl)phosphine–
borane (R)-13 (5.24 g, 84% yield, 92% ee) as a white solid; mp 67–
4.5. Conversion of (S)-tert-butylmethylphosphine–borane (S)-3
into the opposite enantiomer (R)-3
A
solution of (S)-tert-butylmethylphosphine–borane (S)-3
68 °C; ½a 2D5
ꢁ
¼ ꢀ7:5 (c 1.0, CHCl3) >99% ee; 1H NMR (CDCl3) d 0.12–
(590 mg, 5 mmol) in diethyl ether (15 mL) was cooled to ꢀ80 °C
under argon and n-BuLi (3.8 mL of 1.57 M/L hexane solution,
6 mmol) was added with stirring. The temperature was maintained
for 30 min, and then 1,2-dibromoethane (0.69 mL, 8 mmol) was
added to the suspension. The temperature was gradually increased
0.68 (br m, 3H), 1.05 (s, 9H), 1.25 (d, J = 9.9 Hz, 3H), 1.35 (d,
J = 16.1 Hz, 6H), 1.55 (dd, J = 7.7, 2.0 Hz, 2H), 2.04 (m, 1H), 3.92
(ddd, J = 13.1, 7.0, 3.0 Hz, 1H), 4.06 (dd, J = 12.9, 5.7 Hz, 1H). 13C
NMR (CDCl3) d 2.94 (d, J = 34.2 Hz), 22.79, 22.85, 32.04, 32.19 (d,
J = 29.2 Hz), 33.38 (d, J = 8.1 Hz), 47.34, 56.75 (d, J = 36.3 Hz). 31P

T. Imamoto et al. / Tetrahedron: Asymmetry 21 (2010) 1522–1528
1527
NMR (CDCl3)
d
33.54 (m). MS (FAB) m/z 201(M+ꢀ3H), 191
4.10. (R)-Methanesulfonyloxymethyl(methyl)(1,1,3,3-tetra-
methylbutyl)phosphine–borane (R)-14b
(M+ꢀBH3+H). HRMS (TOF): calcd for C10H26BNaOP (M+Na+):
227.1712; found: 227.1717.
To a stirred and cooled (0 °C) mixture of sodium hydride
(72 mg, 3.0 mmol) and (R)-hydroxymethyl(methyl)(1,1,3,3-tetra-
methylbutyl)phosphine–borane (R)-13 (306 mg, 1.5 mmol) was
added THF (4 mL) under nitrogen atmosphere, and stirring was
continued for 30 min at the same temperature. Methanesulfonyl
chloride (0.23 mL, 3.0 mmol) was added and the temperature
was gradually increased to room temperature. After 2 h, the reac-
tion was quenched by the addition of H2O. The mixture was ex-
tracted with EtOAc, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The crude material was
purified by silica gel column chromatography (CH2Cl2/hex-
ane = 20:1) to give (R)-methanesulfonyloxymethyl(methyl)
(1,1,3,3-tetramethylbutyl)phosphine–borane (R)-14b (350 mg,
4.8. (R)-p-Chlorobenzoylmethyl(methyl)(1,1,3,3-tetramethylbu-
tyl)phosphine–borane
To a stirred solution of (R)-hydroxymethyl(methyl)(1,1,3,3-tet-
ramethylbutyl)phosphine–borane (R)-13 (2.04 g, 10 mmol, 92%
ee) and triethylamine (3.34 mL, 24 mmol) in THF (20 mL) was
added dropwise p-chlorobenzoyl chloride (1.54 mL, 12 mmol) at
0 °C. After stirring at room temperature for 2 h, the reaction was
quenched by the addition of H2O. The mixture was extracted with
EtOAc, and the combined extracts were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The sol-
vent was evaporated under reduced pressure and the residual solid
was recrystallized from hexane to give optically pure (R)-p-chloro-
benzoylmethyl(methyl) (1,1,3,3-tetramethylbutyl)phosphine–bor-
ane (2.15 g, 63% yield, >99% ee) as colorless crystals; mp 91–92 °C;
83% yield) as a clear oil; ½a D25
ꢁ
¼ ꢀ14:3 (c 1.0, CHCl3) >99% ee; 1H
NMR (CDCl3) d 0.13–0.66 (br m, 3H), 1.06 (s, 9H), 1.37–1.40 (m,
9H), 1.54 (dd, J = 14.2, 7.8 Hz, 1H), 1.62 (dd, J = 14.2, 8.5 Hz, 1H),
3.10 (s, 3H), 4.44 (dd, J = 13.0, 1.8 Hz, 1H), 4.63 (dd, J = 13.0,
2.4 Hz, 1H). 13C NMR (CDCl3) d 2.73 (m), 3.00 (m), 22.82, 22.88,
32.01, 32.94 (d, J = 29.5 Hz), 33.42 (d, J = 13.1 Hz), 37.38, 47.11
(m), 62.31 (d, J = 29.2 Hz). 31P NMR (CDCl3) d 34.82 (m). MS (FAB)
m/z 281 (M+ꢀH), 269 (M+ꢀBH3+H). HRMS (TOF): calcd for
½
a 2D5
ꢁ
¼ ꢀ9:7 (>99% ee, c 1.0, CHCl3); 1H NMR (CDCl3) d 0.21–0.75
(br m, 3H), 1.05 (s, 9H), 1.36 (d, J = 9.6 Hz, 3H), 1.41 (dd, J = 16.3,
3.0 Hz, 6H), 1.63 (ddd, J = 31.9, 14.1, 7.8 Hz, 2H), 4.70 (dd,
J = 15.8, 1.0 Hz, 1H), 4.77 (dd, J = 14.0, 2.3 Hz, 1H), 7.44
(d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.5 Hz, 2H). 13C NMR (CDCl3) d 3.44
(d, J = 33.2 Hz), 22.84, 22.86, 32.03, 32.71 (d, J = 28.7 Hz), 33.41
(d, J = 13.3 Hz), 47.43, 57.96 (d, J = 35.5 Hz), 127.46, 129.01,
131.11, 140.18, 165.02 (d, J = 4.0 Hz). 31P NMR (CDCl3) d 34.62
(m). MS (FAB) m/z 341 (M+ꢀH), 329 (M+ꢀBH3+H). HRMS (TOF):
C
11H28BNaO3PS (M+Na+): 305.1488; found: 305.1524.
4.11. (S)-Methyl(1,1,3,3-tetramethylbutyl)phosphine–borane
(S)-15
C
17H29BClNaO2P (M+Na+): 365.1584; found: 365.1610. The enan-
To a stirred solution of (R)-hydroxymethyl(methyl)(1,1,3,3-tet-
ramethylbutyl)phosphine-borane (R)-13 (582 mg, 2.85 mmol) in
acetone (5 mL) was added a solution of potassium hydroxide
(1.68 g, 30 mmol) and potassium persulfate (2.31 g, 8.55 mmol)
in water (6 mL). Ruthenium trichloride trihydrate (40 mg,
0.14 mmol) was added to the solution with vigorous stirring at
0 °C. After stirring at room temperature for 2 h, the reaction was
quenched by the addition of 1 M HCl. The mixture was extracted
with EtOAc, washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. The crude material was purified
by silica gel column chromatography (hexane/ethyl acetate = 5:1)
to give (S)-methyl(1,1,3,3-tetramethylbutyl)phosphine–borane
tiomeric excess was determined by HPLC analysis with a chiral
stationary phase column (Daicel Chiralcel AD–H); hexane/i-
PrOH = 99:1, flow rate = 1.0 mL/min, wavelength = 254 nm, t1 =
7.4 min (major), t2 = 8.6 min.
This product was converted into (R)-hydroxymethyl(methyl)
(1,1,3,3-tetramethylbutyl)phosphine-borane (R)-13 on treatment
with 5 M aq KOH solution.
4.9. (R)-p-Toluenesulfonyloxymethyl(methyl)(1,1,3,3-tet-
ramethylbutyl)phosphine–borane (R)-14a
(S)-15 (370 mg, 75% yield) as a clear oil; ½a D25
¼ þ4:7 (c 1.0, CHCl3)
ꢁ
To a stirred and cooled (0 °C) mixture of sodium hydride (48 mg,
2.0 mmol) and (R)-hydroxymethyl(methyl)(1,1,3,3-tetramethylbu-
tyl)phosphine–borane (R)-13 (204 mg, 1.0 mmol) was added THF
(4 mL) under nitrogen atmosphere, and the mixture was stirred
for 30 min at the same temperature. Toluenesulfonyl chloride
(380 mg, 2.0 mmol) was added and the reaction mixture was stirred
for 30 min and then gradually warmed to room temperature. After
2 h, the reaction was quenched by the addition of H2O. The mixture
was extracted with EtOAc, washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The crude material was
purified by silica gel column chromatography (hexane/ethyl
acetate = 7:1) to give (R)-p-toluenesulfonyloxymethyl(methyl)
(1,1,3,3-tetramethylbutyl)phosphine–borane (R)-14a (324 mg,
>99% ee; 1H NMR (CDCl3) d 0.21–0.77 (br m, 3H), 1.05 (s, 9H), 1.30
(dd, J = 10.6, 6.0 Hz, 3H), 1.34 (dd, J = 16.5, 7.2 Hz, 6H), 1.49 (dd,
J = 14.5, 11.5 Hz, 1H), 1.63 (dd, J = 14.5, 9.7 Hz, 1H), 4.41 (dm,
J = 357 Hz, 1H). 13C NMR (CDCl3) d 2.15 (d, J = 34.5 Hz), 24.34,
24.64, 30.65 (d, J = 33.0 Hz), 31.88, 33.24 (d, J = 11.1 Hz), 49.22
(m). 31P NMR (CDCl3) d 18.44 (m).
4.12. (R,R)-Bis(boranato(methyl)(1,1,3,3-tetramethylbutyl)
phosphino)methane 17
To a stirred and cooled (ꢀ78 °C) solution of (S)-methyl(1,1,3,3-
tetramethylbutyl)phosphine–borane (S)-15 (196 mg, 1.13 mmol)
in THF (0.5 mL) was added n-BuLi (0.75 mL of 1.50 M hexane
solution, 1.13 mmol) under a nitrogen atmosphere. After 30 min,
(R)-methanesulfonyloxymethyl(methyl)(1,1,3,3-tetramethylbutyl)
phosphine–borane (R)-14b (350 mg, 1.24 mmol) in THF (1.0 mL)
was added and the solution was heated at 60 °C for 3 h. The mix-
ture was cooled to room temperature and the reaction was
quenched by the addition of H2O. The mixture was extracted with
EtOAc, washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The crude product was purified by silica
gel column chromatography (hexane/ethyl acetate = 20:1),
90% yield) as a clear oil; ½a D25
ꢁ
¼ ꢀ8:3 (c 1.0, CHCl3) >99% ee; 1H
NMR (CDCl3) d 0.00–0.56 (br m, 3H), 1.01 (s, 9H), 1.30–1.34 (m,
9H), 1.41 (dd, J = 14.3, 7.4 Hz, 1H), 1.58 (dd, J = 14.3, 8.8 Hz, 1H),
2.47 (s, 3H), 4.14 (dd, J = 13.0, 1.6 Hz, 1H), 4.42 (dd, J = 13.0,
1.7 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H). 13C
NMR (CDCl3) d 2.45 (d, J = 34.5 Hz), 21.50, 22.62, 22.82, 31.78,
32.76 (d, J = 28.9 Hz), 33.17 (d, J = 13.9 Hz), 46.83 (d, J =
2.3 Hz), 62.59 (d, J = 26.7 Hz), 127.95, 130.03, 131.23, 145.60. 31P
NMR (CDCl3) d 34.31 (m). MS (FAB) m/z 357 (M+ꢀH), 345
(M+ꢀBH3+H).

1528
T. Imamoto et al. / Tetrahedron: Asymmetry 21 (2010) 1522–1528
4. Imamoto, T.; Itoh, T.; Yamanoi, Y.; Narui, R.; Yoshida, K. Tetrahedron: Asymmetry
2006, 17, 560–565.
5. Taira, S.; Crépy, K. V. L.; Imamoto, T. Chirality 2002, 386–392.
6. Ogura, T.; Yoshida, K.; Yanagisawa, A.; Imamoto, T. Org. Lett. 2009, 11, 2245–
2248.
followed by recycling preparative HPLC (CHCl3) to give (R,R)-
bis(boranato(methyl)(1,1,3,3-tetramethylbutyl)phosphino)meth-
ane 17 (159 mg, 39% yield) as a white solid; mp 114–115 °C;
½
a 2D5
ꢁ
¼ ꢀ9:3 (c 1.0, CHCl3) >99% ee; 1H NMR (CDCl3) d 0.27–0.80
7. O’Brien et al. reported that tert-butyldimethylphosphine–borane was subjected
to enantioselective deprotonation on treatment with s-BuLi in the presence of a
catalytic amount of (+)-sparteine surrogate, followed by oxidative dimerization
by CuCl2 to afford the borane adduct of (R,R)-bis(tert-butylmethyl-
(br m, 6H), 1.06 (s, 18H), 1.32 (d, J = 16.5 Hz, 12H), 1.50–1.52 (m,
10H), 1.77 (t, J = 11.8 Hz, 2H). 13C NMR (CDCl3)
d 6.31 (d,
J = 32.8 Hz), 11.97 (t, J = 8.6 Hz), 21.92 (d, J = 4.8 Hz), 32.00, 33.21
(d, J = 12.1 Hz), 33.49 (d, J = 3.8 Hz), 33.73 (d, J = 4.5 Hz), 46.65.
*
phosphino)ethane (t-Bu-BisP ) in 45–59% yield. (a) Genet, C.; Canipa, S. J.;
O’Brien, P.; Taylor, S. J. Am. Chem. Soc. 2006, 128, 9336–9337; (b) Gammon, J. J.;
Canipa, S. J.; O’Brien, P.; Kelly, B.; Yaylor, S. Chem. Commun. 2008, 3750–3752.
8. Gammon, J. J.; O’Brien, P.; Kelly, B. Org. Lett. 2009, 11, 5022–5025.
9. Jackson, M.; Lennon, I. C. Tetrahedron Lett. 2007, 48, 1831–1834.
10. (a) Hoge, G.; Wu, H.-P.; Kissel, W. S.; Pflum, D. A.; Greene, D. J.; Bao, J. J. Am.
Chem. Soc. 2004, 126, 5966; (b) Hoge, G.; Wu, H.-P. Org. Lett. 2004, 6, 3645; (c)
Gridnev, I. D.; Imamoto, T.; Hoge, G.; Kouchi, M.; Takahashi, H. J. Am. Chem. Soc.
2008, 130, 2560–2572.
31P NMR (CDCl3)
d
33.05. MS (FAB) m/z 359 (M+ꢀH), 355
(M+ꢀ6H+H), 345 (M+ꢀBH3ꢀH), 333 (M+ꢀ2BH3+H). HRMS (TOF):
calcd for C19H48B2NaP2 (M+Na+): 383.3315; found: 383.3392.
Acknowledgments
11. Nagata, K.; Matsukawa, S.; Imamoto, T. J. Org. Chem. 2000, 65, 4185–4188.
12. (a) Miura, T.; Yamada, H.; Kikuchi, S.; Imamoto, T. J. Org. Chem. 2000, 65, 1877–
1880; (b) Crépy, K. V. L.; Imamoto, T. Tetrahedron Lett. 2002, 43, 7735–7737.
13. The ee of benzoyl derivative (R)-2 was determined by HPLC analysis using a
chiral column. Daicel Chiralcel OJ–H; hexane/i-PrOH = 9:1, flow rate = 0.5 mL/
min, wavelength = 254 nm, tR = 22.2 min, tS = 24.6 nm.
14. Oohara, N.; Imamoto, T. Bull. Chem. Soc. Jpn. 2002, 75, 1359–1365.
15. Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005, 127, 11934–11935.
16. Imamoto, T.; Saitoh, Y.; Koide, A.; Ogura, T.; Yoshida, K. Angew. Chem., Int. Ed.
2007, 46, 8636–8639.
17. In order to determine the ee of the product, it was converted into the benzyl
derivative on successive treatments with n-BuLi at ꢀ80 °C and benzyl chloride
at the same temperature through room temperature. The product, benzyl(tert-
butyl)methylphosphine–borane, was isolated by column chromatography on
silica gel and was subjected to ee determination. Daicel Chiralcel OD–H;
This work was partly supported by a Grand-in-Aid for Scientific
Research from Ministry of Education, Culture, Sports, Science and
Technology, Japan.
References
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tS = 15.6 min, tR = 17.7 min.
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flow
rate = 0.5 mL/min,
wavelength = 254 nm,