Preparation and use of sterically hindered organobis(2,4,6-triisopropylphenyl)hydroborates and their polystyrene derivatives for the diastereoselective reduction of ketones

Article abstract of DOI:10.1039/a904260a

Preparations of benzyl and phenylbis(2,4,6-triisopropylphenyl)hydroborates [organoditripylhydroborates] are outlined. The lithium and potassium benzylditripylhydroborates reduce substituted cyclohexanones with diastereoselectivities comparable to those obtained with the most selective reagents known (eg. 99% cis-4-methylcyclohexanol from 4-methylcyclohexanone). Lithium phenylditripylhydroborate also reduces ketones with significant selectivity. For example, 4-methylcyclohexanone is reduced to cis-4-methylcyclohexanol in 88% isomeric purity. Unlike with most other highly selective reagents the reactions take place at room temperature and have the additional advantage that the boron reagent can be recovered quantitatively. Coupling of Merrifield's resin with ditripylfluoroborane in the presence of lithium naphthalenide affords (ditripylborylmethyl)polystyrene. Similarly, coupling of bromopolystyrene with ditripylfluoroborane in the presence of n-BuLi affords (ditripylboryl)polystyrene. Reactions of these polymeric organoboranes with t-BuLi give the corresponding polymer-supported lithium hydroborates. Lithium ditripylhydroboratylmethylpolystyrene reduces cyclic ketones in identical fashion to its non-polymeric counterpart, giving the corresponding thermodynamically less stable alcohols in 99% or better isomeric purity. Similarly, lithium ditripylhydroboratylpolystyrene behaves like its non-polymeric counterpart and reduces 4-methylcyclohexanone to cis-4-methylcyclohexanol in 89% isomeric purity. Recovery and reuse of the organoboranes are even easier for the polymeric reagents. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a904260a

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Preparation and use of sterically hindered organobis(2,4,6-
triisopropylphenyl)hydroborates and their polystyrene derivatives
for the diastereoselective reduction of ketones
Keith Smith,*a Gamal A. El-Hiti,†a Duanjie Houa and Gareth A. DeBoosb
a Department of Chemistry, University of Wales Swansea,‡ Swansea, UK SA2 8PP
b ZENECA Huddersfield Works, Huddersfield, UK HD2 1FF
Received (in Cambridge, UK) 27th May 1999, Accepted 12th August 1999
Preparations of benzyl and phenylbis(2,4,6-triisopropylphenyl)hydroborates [organoditripylhydroborates]
are outlined. The lithium and potassium benzylditripylhydroborates reduce substituted cyclohexanones with
diastereoselectivities comparable to those obtained with the most selective reagents known (e.g. 99% cis-4-
methylcyclohexanol from 4-methylcyclohexanone). Lithium phenylditripylhydroborate also reduces ketones with
significant selectivity. For example, 4-methylcyclohexanone is reduced to cis-4-methylcyclohexanol in 88% isomeric
purity. Unlike with most other highly selective reagents the reactions take place at room temperature and have the
additional advantage that the boron reagent can be recovered quantitatively. Coupling of Merrifield’s resin with
ditripylfluoroborane in the presence of lithium naphthalenide affords (ditripylborylmethyl)polystyrene. Similarly,
coupling of bromopolystyrene with ditripylfluoroborane in the presence of n-BuLi affords (ditripylboryl)polystyrene.
Reactions of these polymeric organoboranes with t-BuLi give the corresponding polymer-supported lithium
hydroborates. Lithium ditripylhydroboratylmethylpolystyrene reduces cyclic ketones in identical fashion to its
non-polymeric counterpart, giving the corresponding thermodynamically less stable alcohols in 99% or better
isomeric purity. Similarly, lithium ditripylhydroboratylpolystyrene behaves like its non-polymeric counterpart and
reduces 4-methylcyclohexanone to cis-4-methylcyclohexanol in 89% isomeric purity. Recovery and reuse of the
organoboranes are even easier for the polymeric reagents.
direct analogue of benzylditripylborane, or one derived from
Introduction
bromopolystyrene, which would be a direct analogue of
Highly hindered organoborohydides are very useful reagents
phenylditripylborane. In the present work, therefore, we have
for the diastereoselective reduction of ketones.1 Unhindered
investigated the preparations of benzylditripylborane, phenyl-
reductants such as sodium tetrahydroborate2–4 and borane–
ditripylborane, (ditripylborylmethyl)polystyrene and (ditripyl-
THF5 tend to reduce cycloalkanones to yield the more stable
boryl)polystyrene. We also report hydride transfers from
alcohol by attack from the more hindered face of the molecule.
various sources of hydride to these hindered ditripylborane
As the reductant becomes more hindered6 there is increasing
derivatives and the use of the hydroborates obtained in highly
attack from the less hindered face to give the less stable alcohol.
stereoselective reductions.
The most selective reagents reported for this latter process
are lithium tri-sec-butylhydroborate,7 lithium tris(1,2-di-
methylpropyl)hydroborate (lithium trisiamylhydroborate)8 and
lithium ethylbis(2,4,6-triisopropylphenyl)hydroborate [lithium
ethylditripylhydroborate].9
Results and discussion
Benzylditripylborane (1) was prepared in 71% purified yield
by reaction of ditripylfluoroborane10 and benzylmagnesium
chloride in THF under reflux for 3 h, in a manner similar to that
used previously for the preparation of ethylditripylborane.
Moreover, formation of benzyllithium by treatment of benzyl
chloride with lithium naphthalenide in diethyl ether–tetra-
hydrofuran–light petroleum (bp 30–40 ЊC) (4:3:1),11 followed
by reaction with ditripylfluoroborane, gave benzylditripyl-
borane (1) in 67% yield. However, when a mixture of benzyl
chloride and ditripylfluoroborane was treated in situ with lith-
ium naphthalenide in THF, this one step procedure afforded
benzylditripylborane (1) in even better yield (81%). The one
step procedure is therefore recommended for the synthesis of 1,
since it is both simpler and provides a higher yield.
Attempted preparation of sodium benzylditripylhydroborate
by reaction of 1 with sodium hydride or sodium borohydride
was not successful due to incomplete hydride transfer to the
borane reagent. Lithium aluminium hydride was more success-
ful, but the 11B NMR spectrum of the resultant mixture showed
that ditripyldihydroborate was formed as well as benzylditripyl-
hydroborate, apparently as a result of debenzylation of 1 or its
hydroborate derivative under the reaction conditions.
There are advantages associated with the use of lithium
ethylditripylhydroborate, because it works at room temperature
and the parent organoborane is stable in solution, stable to
water and air, and can be recovered quantitatively after the
reduction. By contrast, the procedures used for other boron
reagents, such as tri-sec-butylhydroborates,7 require low tem-
perature (Ϫ78 ЊC) to provide a high selectivity for some cyclic
ketones, and result in complete degradation of the organo-
borane during work up. Therefore, we have sought to build on
the advantages of the alkylditripylborane derivative by generat-
ing more hindered organoboranes, e.g. benzyl and phenyl-
ditripylboranes and their polymeric analogues. Moreover, it
was anticipated that the polymeric analogues would have the
additional advantage of ease of recovery by filtration, without
the need for column chromatography.
The most easily accessible polymeric analogue appeared to
be one derived from the Merrifield resin, which would be a
† Permanent address: Department of Chemistry, Faculty of Science,
Tanta University, Tanta, Egypt.
‡ Formerly known as the University College of Swansea.
J. Chem. Soc., Perkin Trans. 1, 1999, 2807–2812
This journal is © The Royal Society of Chemistry 1999
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Table 1 Diastereoselectivities in reduction of cyclic ketones with
potassium ditripylbenzylhydroborate (5)
Our attention was turned next to the use of potassium triiso-
propoxyborohydride and tetrabutylammonium borohydride as
hydride sources. 11B NMR showed that hydride transfer was
successful in these cases, the corresponding benzylditripyl-
hydroborates being formed in essentially quantitative yields.
However, when solutions of the hydroborates generated in situ
in this way were used for reduction of cyclohexanones,
although the reactions gave excellent yields of the correspond-
ing alcohols the stereoselectivity was low, presumably due
to competitive reduction by potassium triisopropoxyboro-
hydride12 or tetrabutylammonium borohydride13 present in
equilibrium with the benzylditripylhydroborate.
Our attention was therefore turned next to the use of t-BuLi
as a hydride source.1b Indeed, addition of t-BuLi to 1 gave
lithium benzylditripylhydroborate (2), which reduced 4-methyl-
cyclohexanone and 4-tert-butylcyclohexanone to cis-4-
methylcyclohexanol and cis-4-tert-butylcyclohexanol in 99%
and >99% isomeric purity, respectively (Scheme 1).
% of less
stable
Yield
(%)b
Ketone
Alcohol
alcohola
2-Methylcyclopentanone
2-Methylcyclohexanone
3-Methylcyclohexanone
4-Methylcyclohexanone
4-tert-Butylcyclohexanone
cis
cis
trans
cis
cis
>99
85
90
87
93
97
>99
>99
99
>99
a GC indicated that the reactions were all essentially quantitative.
b Yield of isolated, purified product.
Scheme 3
and then work up, gave the corresponding cyclic alcohol with a
very high cis- to trans- ratio (Table 1).
As shown in Table 1, potassium benzylditripylhydroborate
(5) completely reduces 2-methylcyclopentanone, 2-methylcyclo-
hexanone, 3-methylcyclohexanone, 4-methylcyclohexanone and
4-tert-butylcyclohexanone with very high stereoselectivities,
comparable with those obtained using the most selective
reagents known, but without the requirement for low temper-
atures needed by several other systems.6,7
Scheme 1
In view of the ease of conversion of 1 into its potassium
hydroborate derivative and the ease of reduction of ketones
by the latter reagent, it appeared possible that 1 could be used
to catalyse the direct KH reduction of cyclic ketones. A series
of experiments was therefore conducted in which a catalytic
amount of 1 and excess potassium hydride were used in
attempts to reduce 4-substituted cyclohexanones directly.
Indeed, the 4-substituted cyclohexanones were reduced in
excellent yields to the corresponding alcohols, but the diastereo-
selectivities were low, presumably due to formation of ditripyl-
borane as a result of debenzylation of 1 under the influence of
the excess KH present. Similar observations were made in the
case of ethylditripylborane.9
Our success in the stereoselective reduction of ketones using
2 prompted us to prepare other hindered organoboranes.
Phenylditripylborane (3) was prepared in 80% yield after crys-
tallisation by reaction of ditripylfluoroborane10 and phenyl-
lithium in light petroleum (bp 30–40 ЊC) for 26 h at room
temperature. In a manner similar to that used previously for the
preparation of 2, lithium phenylditripylhydroborate (4) was
prepared by addition of t-BuLi to 3. Reduction of 4-methyl-
cyclohexanone using 4 gave cis-4-methylcyclohexanol in 88%
isomeric purity (Scheme 2). The selectivity of this reagent is
Our investigations thus far had shown that both lithium and
potassium benzylditripylhydroborates 2 and 5 are amongst the
most selective reagents known for reduction of cyclohexanones,
and that the corresponding organoborane, 1, can be recovered
quantitatively after reduction. However, because of their high
molecular weights large quantities of reagent are required for
such reductions. Moreover, separation of product and organo-
borane reagent by column chromatography after reaction
would be a major problem for large-scale use. By contrast,
polymer-supported reagents have the advantage of allowing
separation of insoluble polymeric by-products from the reac-
tion mixtures by filtration.15 In some cases the polymeric
reagents can be regenerated. It was therefore of interest to
investigate the use of polymer-supported analogues of the
boron reagents 1 and 3 for selective reductions.
Chloromethylpolystyrene (Merrifield’s resin) and bromo-
polystyrene are readily available commercial polymers and we
decided to use these to generate functionalised polymers. A
convenient method for the preparation of organylditripyl-
boranes involves the reaction of ditripylfluoroborane with a
reactive organometallic reagent such as an organolithium or
organomagnesium reagent.9 Therefore, we proposed to try to
functionalise the commercial resins by this route.
Scheme 2
therefore rather lower than that of lithium ethylditripyl-
hydroborate9 or lithium benzylditripylhydroborate (see above).
A possible reason is that triarylboranes tend to form radical
anions, which may lower the stereoselectivity.14
Our attention was turned next to the use of KH as a hydride
source in the hope of obtaining potassium benzylditripyl-
hydroborate (5) for use in selective reductions. Indeed, addition
of a THF solution of 1 to a THF suspension of activated KH
afforded potassium benzylditripylhydroborate (5) within less
than five minutes. Addition of a THF solution of a substituted
cyclohexanone into the THF solution of 5 at room temperature
(Scheme 3), followed by stirring overnight at room temperature
There is no report in the literature concerning preparation of
the lithium derivative of Merrifield’s resin, although the mag-
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Table 2 Diastereoselectivities in reduction of cyclic ketones with
lithium ditripylhydroboratylmethylpolystyrene (9)
As shown in Table 2, polymer 9 completely reduces 2-methyl-
cyclopentanone, 2-methylcyclohexanone, 3-methylcyclo-
hexanone, 4-methylcyclohexanone, 4-tert-butylcyclohexanone,
(Ϫ)-menthone and benzoin with very high stereoselectivities,
again comparable with those obtained using the most selective
reagents known, but without the requirement for low temper-
atures needed by several other systems.6,7
The polymer 8 could be separated and purified from the
reduction product by simple filtration on a fritted funnel and
washing with THF. Recovered 8 behaved in the same way as
original 8, even when 8 was reused several times. Overall, there-
fore, polymer 8 acts as a mediator for the selective reduction of
ketones by tert-butyllithium (Scheme 5).
% of less
stable
Yield
(%)b
Ketone
Alcohol
alcohola
2-Methylcyclopentanone
2-Methylcyclohexanone
3-Methylcyclohexanone
4-Methylcyclohexanone
4-tert-Butylcyclohexanone
cis
cis
trans
cis
cis
>99
85
90
89
91
96
>99
>99
99
>99
Our attention was turned next to the preparation of
(ditripylboryl)polystyrene (12) and its use in stereoselective
reductions. Lithiated polystyrene 11 is a useful intermediate
in the preparation of numerous other functional polymers.17,18
Initially, the ditripylborylpolystyrene 12 was prepared by the
method shown in Scheme 6. Reaction of bromopolystyrene 10
>99
92
>99
88
a GC indicated that the reactions were all essentially quantitative.
b Yield of isolated, purified product.
nesium derivative has been prepared.16 Our successful gener-
ation of benzyllithium from benzyl chloride11 prompted us to
attempt preparation of ditripylborylmethylpolystyrene (8)
under similar conditions.
Polymer 8 was indeed conveniently prepared via lithio-
methylpolystyrene (7). The addition of excess of lithium naph-
thalenide in THF to a mixture of Merrifield’s resin (6) and
ditripylfluoroborane (molar ratio of Cl to Trip2BF 1:1.5) in
THF at Ϫ78 ЊC afforded polymer 8 in a functional yield of 75%
(Scheme 4). In view of its stability in air, polymer 8 was readily
Scheme 6
with concentrated n-butyllithium (10 mol dmϪ3)19 in benzene
afforded polystyryllithium 11, which was treated with
ditripylfluoroborane9 in THF to give 12 in a functional yield of
66%. The second step reaction from 11 to 12 worked smoothly
in THF at room temperature, but the reaction gave a low yield
(23%) in benzene.
Treatment of a suspension of 12 in THF with tert-butyl-
lithium at room temperature afforded the corresponding
lithium hydroborate 13, which reduced 4-methylcyclohexanone
to cis-4-methylcyclohexanol of 89% purity (Scheme 7). This
Scheme 4
purified by simple filtration on a fritted funnel and washing
with a series of solvents.
Treatment of a suspension of 8 in THF with tert-butyl-
lithium at room temperature afforded the corresponding lith-
ium hydroborate 9, which completely reduced representative
ketones (Scheme 5) in 99% or better isomeric purity. The results
are shown in Table 2.
Scheme 7
result is very similar to the result from the reaction with lithium
phenylditripylhydroborate (4).
Conclusion
Lithium and potassium benzylditripylhydroborates reduce rep-
resentative ketones with high diastereoselectivities compared
Scheme 5
J. Chem. Soc., Perkin Trans. 1, 1999, 2807–2812
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with most other stereoselective reagents. Moreover, reactions
are carried out at room temperature and the organoborane
reagent can be recovered quantitatively.
Preparation of benzylbis(2,4,6-triisopropylphenyl)borane (1) via
benzyl chloride (in two steps)
A solution of benzyl chloride (0.324 g, 2.56 mmol) in diethyl
ether (8 cm3), THF (6 cm3) and light petroleum (bp 30–40 ЊC)
(2 cm3) was added via a double ended needle to a stirred
solution of lithium naphthalenide (1.0 mol dmϪ3; 6.78 cm3,
6.78 mmol) in THF over a period of 15 minutes (lithium
naphthalenide was prepared by stirring a solution of naphthal-
ene in THF with lithium metal at 0 ЊC for 6 h). The resultant
mixture was stirred for a further 15 min at Ϫ95 ЊC, after which
bis(2,4,6-triisopropylphenyl)fluoroborane (2.4 g, 5.5 mmol) in
diethyl ether (6 cm3) was added dropwise at Ϫ78 ЊC. The mix-
ture was stirred at Ϫ78 ЊC for 20 min, then stirred overnight at
room temperature. Crystallisation of the crude product from
methanol after work up afforded 1 (1.87 g, 3.68 mmol, 67%) as
white crystals.
Polymeric analogues of benzyl- and phenyl-ditripylboranes
have been successfully prepared from Merrifield’s resin and
bromopolystyrene, respectively, and have then been converted
into their hydroborates by the use of tert-butyllithium. The
polymeric hydroborates are also very selective reagents for the
diastereoselective reduction of ketones, comparable with their
non-polymeric counterparts. The organoborane polymers have
the additional advantage that they can be recovered easily by
filtration and without the need for chromatography. They
should therefore prove attractive for larger scale work. The
polymer derived from Merrifield’s resin should be particularly
attractive in view of the very high stereoselectivities exhibited in
reactions using its hydroborate derivative.
Preparation of benzylbis(2,4,6-triisopropylphenyl)borane (1) via
benzyl chloride (in one step)
Experimental
1H and 11B NMR spectra were recorded on a Bruker spec-
trometer operating at 400 MHz for H, 100 MHz for 13C and
1
To a cooled solution (Ϫ78 ЊC) of lithium naphthalenide (1.0
mol dmϪ3; 12.5 cm3, 12.5 mmol) in THF under nitrogen, a solu-
tion of bis(2,4,6-triisopropylphenyl)fluoroborane (1.95 g, 4.47
mmol) and benzyl chloride (0.354 g, 2.79 mmol) in THF (50
cm3) was added dropwise. The mixture was stirred at Ϫ78 ЊC for
6 h and at room temperature for 16 h. The mixture was diluted
with diethyl ether (60 cm3) then quenched with water (5 cm3).
The organic layer was separated and washed with NH4Cl (3 ×
6 cm3). The extracts were dried (MgSO4) and the solvent was
removed under reduced pressure. The residue obtained was
purified by crystallisation from methanol to give 1 (1.84 g, 3.62
mmol, 81%) as white crystals.
128 MHz for 11B measurements. Low resolution mass spectra
were recorded on a VG 12-253 spectrometer, electron impact
(EI) at 70 eV and chemical ionization (CI) by use of ammonia
as ionizing gas. Accurate mass data were obtained on a VG
ZAB-E instrument. Column chromatography was carried out
using Merck Kieselgel 60 (230–400 mesh). tert-Butyllithium
and cyclic ketones were obtained from Aldrich Chemical Com-
pany and t-BuLi was estimated prior to use by the method of
Watson and Eastham.20 Bromopolystyrene and chloromethyl-
polystyrene (Merrifield resin) were obtained from Fluka
Chemical Company. THF was distilled from sodium benzo-
phenone ketyl. Other chemicals were obtained from Aldrich
Chemical Company and used without further purification.
Solvents were purified by standard procedures.21,22
Preparation of lithium benzylbis(2,4,6-triisopropylphenyl)hydro-
borate (2) using t-BuLi, and its use for selective reduction of
4-substituted cyclohexanones
Preparation of benzylbis(2,4,6-triisopropylphenyl)borane (1) via
benzylmagnesium chloride
A dry 100 cm3 round-bottomed flask connected to a bubbler
was charged with 1 (1.02 g, 2.0 mmol) and then flushed for 5
min with nitrogen. Tetrahydrofuran (20 cm3) was added and the
solution was stirred whilst tert-butyllithium (1.7 mol dmϪ3; 1.2
cm3, 2.0 mmol) was added slowly by syringe. The resulting solu-
tion was stirred for 10 min at room temperature, after which it
showed a doublet in its 11B NMR spectrum at δ = Ϫ13.94 (d,
J = 77.9 Hz), which collapsed to a singlet on decoupling the
proton signals. A solution of 4-substituted cyclohexanone (1.0
mmol) in THF (5 cm3) was added and the mixture was stirred
overnight at room temperature. The reaction mixture was
quenched with a mixture of water (10 cm3) and diethyl ether (10
cm3) and the separated organic layer was washed further with
brine (3 × 20 cm3). The aqueous layers were combined and then
washed with ether (20 cm3). The organic layers were combined,
dried (MgSO4), and filtered and the solvent was then removed
under reduced pressure. The residue was transferred to a dry
silica gel column and eluted with light petroleum (30–40 ЊC)
to give recovered benzylbis(2,4,6-triisopropylphenyl)borane
(1) (~0.94–0.96 g, ~94–96%). The column was then eluted with
light petroleum (bp 30–40 ЊC)–diethyl ether mixture (50:50→
0:100) until the product had completely eluted to give the
corresponding alcohol. The GC results are given in Scheme 1.
The recovered benzylbis(2,4,6-triisopropylphenyl)borane was
used for a repeat of the same reaction and gave the same
results.
A dry 100 cm3, two-necked round-bottomed flask equipped
with a reflux condenser and magnetic follower was charged with
bis(2,4,6-triisopropylphenyl)fluoroborane (2.05 g, 4.7 mmol).
The flask was purged with nitrogen and warmed for several
minutes with a hair dryer. THF (10 cm3) was added and the
resulting solution cooled in an ice bath. A solution of benzyl-
magnesium chloride (8 cm3, 14.1 mmol) was added using a
syringe. Once addition was complete the coolant was removed
and the mixture was stirred at room temperature for 30 min,
then under reflux for 3 h, then for 16 h at room temperature.
The mixture was quenched with saturated ammonium chloride
solution (5 cm3); diethyl ether (30 cm3) was added, and the
layers were separated. The organic layer was washed with brine
(2 × 30 cm3) and the combined aqueous layers were extracted
with a portion of fresh ether (20 cm3). The combined ether
portions were dried (MgSO4), filtered and concentrated under
reduced pressure. The residue obtained was recrystallised from
methanol to give 1 (1.70 g, 3.35 mmol, 71%) as white crystals.
Mp 95–96 ЊC; δH(CDCl3) 7.10–7.03 (m, 5 H, Ph), 6.94 (s, 4 H,
ArH), 3.47 (br s, 2 H, CH2), 2.85 [m, 6 H, 6 × CH(CH3)2], 1.23
[d, J 6.9 Hz, 12 H, 2 × CH(CH3)2] and 0.98 [br d, 24 H,
4 × CH(CH3)2]; δC(CDCl3) 150.10 (s, C-2), 149.67 (s, C-4),
142.30 (s, C-1), 140.31 (s, C-1 of Ph), 129.65 (d, C-2 of Ph),
127.91 (d, C-3 of Ph), 124.72 (d, C-4 of Ph), 121.13 (d, C-3),
42.26 (t, CH2), 34.16 [d, 2 × CH(CH3)2], 33.72 [d, 4 ×
CH(CH3)2], 24.53 [q, 2 × CH(CH3)2] and 23.92 [q, 4 × CH-
(CH3)2]; δB(CDCl3) 83.83; m/z (EI) 508 (Mϩ, 0.4%), 416 (30),
213 (18), 203 (13), 189 (8), 169 (10), 91 (95) and 43 (100); m/z
Preparation of phenylbis(2,4,6-triisopropylphenyl)borane (3)
A dry 100 cm3, two-necked round-bottomed flask equipped
with a reflux condenser and magnetic follower was charged with
bis(2,4,6-triisopropylphenyl)fluoroborane (2.09 g, 4.8 mmol).
The flask was purged with nitrogen and warmed for several
minutes with a hair dryer. Light petroleum (bp 30–40 ЊC)
ϩ
(CI) 526 (M ϩ NH4 , 100%), 417 (35), 322 (44), 305 (27),
ϩ
203 (8) and 91 (5) (Found: M ϩ NH4 , 526.4584. Calc. for
C37H57NB: 526.4584).
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(10 cm3) was added and the resultant solution was cooled in an
ice bath. A solution of phenyllithium (1.0 mol dmϪ3; 9.6 cm3,
9.6 mmol) was added using a syringe and the mixture was then
allowed to warm up and stirred for 26 h at room temperature.
The reaction was carefully quenched by the addition of a mix-
ture of diethyl ether (20 cm3) and water (20 cm3). The organic
layer was washed with water (2 × 10 cm3), dried (MgSO4), and
filtered and the solvent was removed under reduced pressure.
The crude product obtained was recrystallised from methanol
to give 3 (1.83 g, 3.70 mmol, 80%) as white crystals. Mp 117–
118 ЊC; δH(CDCl3) 7.46–7.30 (m, 5 H, Ph), 6.96 (s, 4 H, ArH),
2.98–2.84, 2.50–2.35 [2 m, 6 H, 6 × CH(CH3)2], 1.25 [d, J 6.9
Hz, 12 H, 2 × CH(CH3)2] and 1.15, 0.68 [2 br s, 24 H,
4 × CH(CH3)2]; δC(CDCl3) 151.39 (s, C-4), 149.58 (s, C-2),
149.05 (s, C-1 of Ph), 141.60 (s, C-1), 135.42 (d, C-2 of Ph),
131.00 (d, C-4 of Ph), 127.26 (d, C-3 of Ph), 121.71, 119.99 (2 d,
C-3), 34.47, 34.18, 33.48 [3 d, 3 × CH(CH3)2] and 24.89, 23.93,
23.69 [3 q, 3 × CH(CH3)2]; δB(CDCl3) 77.55; m/z (EI) 290
and then with light petroleum (bp 30–40 ЊC)–diethyl ether mix-
ture (50:50→0:100) until the product alcohol had completely
eluted (85–97% isolated yields). Isomer proportions were esti-
mated by GC. The results are given in Table 1.
Preparation of bis(2,4,6-triisopropylphenyl)borylmethyl-
polystyrene (8)
To a suspension of 1% cross-linked chloromethylpolystyrene (6)
(0.80 g, 1.36 mmol Cl) and bis(2,4,6-triisopropylphenyl)fluoro-
borane (0.86 g, 2.06 mmol) in THF (25 cm3) under nitrogen at
Ϫ78 ЊC was added lithium naphthalenide (1.0 mol dmϪ3; 5.8
cm3, 5.8 mmol) rapidly. The mixture was stirred at Ϫ78 ЊC for
6 h then at room temperature for 15 h. The reaction was
quenched with aqueous saturated ammonium chloride solution
(5 cm3), then filtered. The polymer was washed with H2O, Et2O,
THF–H2O (2:1), H2O, THF and Et2O three times and dried
at 50 ЊC under vacuum for 8 h to give the boron polymer 8
(1.12 g).
ϩ
(20%), 247 (100) and 169 (30); m/z (CI) 512 (M ϩ NH4 , 16%),
ϩ
495 (MHϩ, 3) and 308 (100) (Found: M ϩ NH4 , 512.4427.
Titration of bis(2,4,6-triisopropylphenyl)borylmethylpolystyrene
(8)
Calc. for C36H55NB: 512.4427).
Preparation of lithium phenylbis(2,4,6-triisopropylphenyl)hydro-
borate (4) using t-BuLi, and its use for selective reduction of
4-methylcyclohexanone
An oven-dried 50 cm3 round-bottomed flask equipped with a
nitrogen inlet and a glass-coated magnetic bar was flushed with
nitrogen and charged with bis(2,4,6-triisopropylphenyl)boryl-
methylpolystyrene (8) (1.12 g) in THF (10 cm3). A solution of
tert-butyllithium (1.7 mol dmϪ3; 1.0 cm3, 1.7 mmol) in pentane
was added. There was a gently exothermic reaction and the
mixture was stirred for 30 min at room temperature. After
removal of the liquid phase with a double-ended needle, the
polymer was washed with dry THF (3 × 10 cm3). The combined
THF washing was titrated against 0.2 M HCl. The titration
showed that 0.2 M HCl (3.4 cm3, 0.68 mmol) was used. This
showed that 1.02 mmol of tert-butyllithium (1.70 Ϫ 0.68 = 1.02
mmol) had reacted with the polymer indicating that the poly-
mer contained 0.91 mmol gϪ1 of boron and that the functional
yield was 75% (1.02 mmol from 1.36 mmol).
With the same procedure as for lithium benzylbis(2,4,6-triiso-
propylphenyl)hydroborate 2, a brown solution of lithium
phenylbis(2,4,6-triisopropylphenyl)hydroborate (4) (0.99 g, 2.0
mmol) was prepared. 4-Methylcyclohexanone (0.11 g, 1.0
mmol) was added and reduced to cis-4-methylcyclohexanol in
88% isomeric purity (i.e. a ratio of cis- to trans- isomers 88:12).
The recovered yield of phenylbis(2,4,6-triisopropylphenyl)-
borane (3) was 89% and the isolated yield of 4-methylcyclo-
hexanol was 83%.
General procedure for the preparation of potassium benzylbis-
(2,4,6-triisopropylphenyl)hydroborate (5) using potassium
hydride, and its selective reduction of cyclic ketones
Preparation of lithium bis(2,4,6-triisopropylphenyl)hydro-
boratylmethylpolystyrene (9) and its use for selective reduction
of ketones
An oven-dried 100 cm3 round-bottomed flask equipped with
a nitrogen inlet and a glass-coated magnetic bar was charged
with potassium hydride (0.30 g of a 35% oil dispersion, 2.62
mmol) and flushed with nitrogen. Light petroleum (30–40 ЊC,
3 × 15 cm3) was added and the mixture was stirred for 20
minutes. The suspension was allowed to settle, and then the
solvent was removed through a double-ended needle. A solu-
tion of LiAlH4 was prepared by stirring the solid (2.5 g) in
THF (100 cm3) for 16 h. A sample of the supernatant
(10 cm3, containing about 2.94 mmol of LiAlH4) was added
to the KH, the suspension was stirred for 30 min, and the
supernatant was then removed. The solid residue was
washed with THF (10 cm3) and then suspended in THF (10
cm3). Benzylbis(2,4,6-triisopropylphenyl)borane (1) (1.0 g, 2.0
mmol) in THF (10 cm3) was added. There was a gently exo-
thermic reaction, and the mixture was stirred for 10 min at
room temperature. The resultant solution showed a doublet
in the 11B NMR spectrum at δ = Ϫ13.91 (d, J = 78.9 Hz),
which collapsed to a singlet on decoupling the proton signals.
The solution so prepared was transferred by a double-ended
needle to a stirred solution of cyclic ketone (1.0 mmol) in
THF (5 cm3) and the mixture was stirred overnight at room
temperature. The reaction mixture was quenched with a mix-
ture of water (5 cm3) and diethyl ether (5 cm3) and the separ-
ated organic layer washed further with brine (2 × 10 cm3).
The combined aqueous extracts were washed with ether (20
cm3), the combined organic layers were dried (MgSO4) and
filtered, and the solvent was removed under reduced pressure.
The residue was transferred to a dry silica gel column and
eluted with light petroleum (bp 30–40 ЊC) to give benzyl-
bis(2,4,6-triisopropylphenyl)borane (~0.94–0.97 g, ~94–97%)
An oven-dried 50 cm3 round-bottomed flask equipped with a
nitrogen inlet and a glass-coated magnetic bar was charged with
bis(2,4,6-triisopropylphenyl)borylmethylpolystyrene (8) (1.12
g) in THF (10 cm3) and flushed with nitrogen. A solution of
tert-butyllithium (1.7 mol dmϪ3; 1.0 cm3, 1.7 mmol) in pentane
was added slowly by syringe. There was a gently exothermic
reaction and the mixture was stirred for 30 min at room tem-
perature. After removal of the liquid phase with a double-ended
needle, the polymer was washed with dry THF (3 × 10 cm3) and
suspended in dry THF (10 cm3). A solution of the appropriate
ketone (0.78 mmol) in THF (5 cm3) was added and the mixture
was stirred overnight at room temperature and then filtered.
The solid was washed with THF (3 × 10 cm3) and dried, ready
to be reused for other reductions. The filtrate and washings
were combined and a mixture of water (5 cm3) and diethyl ether
(5 cm3) was added. After separation, the organic layer was dried
(MgSO4) and the solvent was removed under reduced pressure.
The GC results are shown in Table 2. Simple removal of the
solvent gave the corresponding alcohol in 85–96% isolated
yield.
Preparation of bis(2,4,6-triisopropylphenyl)borylpolystyrene (12)
A dry 50 cm3, round-bottomed flask equipped with a magnetic
follower was charged with bromopolystyrene 10 (0.66 g, 2.64
mmol Br) then flushed with nitrogen. Benzene (15 cm3) was
added and the suspension was stirred at room temperature for
30 min then n-butyllithium (10 mol dmϪ3; 0.8 cm3, 8.0 mmol)
was slowly added by syringe. The mixture was stirred at room
J. Chem. Soc., Perkin Trans. 1, 1999, 2807–2812
2811

View Article Online
(b) A. Pelter, K. Smith and H. C. Brown, Borane Reagents,
Academic Press, London, 1988; (c) R. S. Atkinson, Stereoselective
Synthesis, John Wiley & Sons, Chichester, 1995.
temperature for 30 min and then stirred at 65–69 ЊC for 4 h.
After removal of the liquid phase and washing with dry THF
(3 × 10 cm3), dry THF (7 cm3) was added to the lithiated poly-
styrene 11, the mixture was cooled to 0 ЊC and a solution of
bis(2,4,6-triisopropylphenyl)fluoroborane (1.15 g, 2.64 mmol)
in THF (7 cm3) was added. The mixture was allowed to warm to
room temperature and stirred for 15 h, and then stirred for 5.5 h
at 50–56 ЊC. The resin was collected on a filter and washed
successively with THF, Et2O, THF–H2O (2:1), H2O, THF and
finally MeOH. After drying under reduced pressure, polymer 12
(1.16 g) was obtained in 66% functional yield as measured by
titration.
2 E. C. Ashby and J. R. Boone, J. Org. Chem., 1976, 41, 2890.
3 D. C. Wigfield and D. J. Phelps, J. Org. Chem., 1976, 41, 2396.
4 D. C. Wigfield, Tetrahedron, 1979, 35, 449.
5 H. C. Brown and V. Varma, J. Am. Chem. Soc., 1974, 39, 1631.
6 H. C. Brown and W. C. Dickason, J. Am. Chem. Soc., 1970, 92, 709.
7 H. C. Brown and S. Krishnamurthy, J. Am. Chem. Soc., 1972, 94,
7159; H. C. Brown, J. Am. Chem. Soc., 1973, 95, 4100.
8 H. C. Brown and S. Krishnamurthy, J. Am. Chem. Soc., 1976, 98,
3383.
9 K. Smith, A. Pelter and A. Norbury, Tetrahedron Lett., 1991, 32,
6243.
10 A. Pelter, K. Smith, D. Buss and A. Norbury, Tetrahedron Lett.,
1991, 32, 6239.
Preparation of lithium bis(2,4,6-triisopropylphenyl)hydro-
boratylpolystyrene (13) and its use for selective reduction of
4-methylcyclohexanone
11 K. Smith and D. Hou, J. Chem. Soc., Perkin Trans. 1, 1995, 185.
12 C. A. Brown, J. Org. Chem., 1974, 39, 3913; H. C. Brown, B. Nazer
and J. A. Silkorski, Organometallics, 1983, 2, 634; H. C. Brown,
J. S. Cha and B. Nazer, Inorg. Chem., 1984, 23, 2929; J. A.
Soderquist and I. Rivera, Tetrahedron Lett., 1988, 29, 3195.
13 J. Seyden-Penne, in Reductions by the Alumino- and Borohydrides in
Organic Synthesis, ed. D. P. Curran, Wiley-VCH, New York, 1997.
14 H. C. Brown, G. W. Kramer, J. L. Hubbard and S. Krishnamurthy,
J. Organomet. Chem., 1980, 188, 1.
15 Solid Supports and Catalysts in Organic Synthesis, ed. K. Smith, Ellis
Horwood, Chichester, 1992; J. M. J. Fréchet, Tetrahedron, 1981, 37,
663; A. Akelah and D. C. Sherrington, Chem. Rev., 1981, 81, 557.
16 S. Itsuno, G. D. Darling, H. D. H. Stover and J. M. J. Fréchet, J. Org.
Chem., 1987, 52, 4644.
With the same procedure as for polymer 9, polymer 13 was
prepared as a deep red coloured solid by treatment of bis(2,4,6-
triisopropylphenyl)borylpolystyrene (12) (1.16 g) in THF with
tert-butyllithium (1.7 mol dmϪ3; 1.0 cm3, 1.7 mmol) at room
temperature. Polymer 13 reduced 4-methylcyclohexanone to
cis-4-methylcyclohexanol in 89% stereoselectivity. The GC yield
of 4-methylcyclohexanol was 96% and the isolated yield was
90%.
17 M. J. Farral and J. M. J. Fréchet, J. Org. Chem., 1976, 41, 3877.
18 M. Bernard and W. T. Ford, J. Org. Chem., 1983, 48, 326.
19 These are conditions developed in our laboratory for other purposes
by M. Tzimas; lithiation with concentrated n-butyllithium is more
complete than with a dilute solution.
20 S. C. Watson and J. F. Eastham, J. Organomet. Chem., 1967, 9, 165.
21 Vogel’s Textbook of Practical Organic Chemistry, 5th edn.,
Longman, Harlow, 1989.
Acknowledgements
G. A. El-Hiti thanks ZENECA for financial support and the
Royal Society of Chemistry for an international author grant.
We thank the EPSRC and the University of Wales for grants
that enabled the purchase of NMR equipment used in the
course of this work.
22 D. D. Perrin and W. L. F. Armarego, Purification of Laboratory
Chemicals, Pergamon, 3rd edn., Butterworth Heinemann, Oxford,
1988.
References
1 (a) K. Smith, in Organometallics in Synthesis, ed. A. Manual and
M. Schlosser, John Wiley & Sons, Chichester, 1994, pp. 461–508;
Paper 9/04260A
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J. Chem. Soc., Perkin Trans. 1, 1999, 2807–2812