Synthesis of dihydrobenzazaphosphole ligands via an intramolecular cyclisation reaction

Article abstract of DOI:10.1039/b105495n

Intramolecular cyclization reaction of 1,3,2-oxazaphospholidines was used for the diastereoselective synthesis of dihydrobenzazaphosphole ligands. These ligands can be employed in either monodonor or bidentane form in asymmetric reactions such as palladium-catalyzed allylic substitution. Synthesis of the C₂symmetric diphosphine ligand 9 was also discussed.

Full text of DOI:10.1039/b105495n

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Synthesis of dihydrobenzazaphosphole ligands via an
intramolecular cyclisation reaction
Wilson Leung,a Sarah Cosway,a Raymond H. V. Jones,b Hannah McCannb and Martin Willsa
1
a Department of Chemistry, University of Warwick, Coventry, UK CV4 7AL
b Process Technology Department, Zeneca FCMO, Earls Road, Grangemouth, Stirlingshire,
UK FK3 8XG
Received (in Cambridge, UK) 21st June 2001, Accepted 21st August 2001
First published as an Advance Article on the web 21st September 2001
A novel intramolecular cyclisation reaction of 1,3,2-oxazaphospholidines has been employed for the
diastereoselective synthesis of chiral, non-racemic dihydrobenzazaphosphole ligands. The new ligands
have been employed in enantioselective palladium-catalysed allylic substitution reactions.
We anticipated that such ligands would benefit from simple
modification towards a number of mono- and bidentate deriv-
atives which could be ‘fine-tuned’ towards certain reactions by
variation of the functional group X and the exocyclic phos-
phorus donor group.
Introduction
Enantiomerically pure bidentate phosphorus-donor ligands are
pivotal materials in asymmetric catalysis.1 Whilst C2 symmetric
ligands such as Chiraphos 1, BINAP and DiPAMP have the
advantage of simplicity of structure, mixed-donor unsymmetric
ligands have the advantage of versatility in terms of electronic
and steric structure. An electronic change can have a dramatic
effect; for example the enantioselectivity of asymmetric hydro-
genation (Scheme 1) may increase markedly when the ligand
Previous work in our group5 had led to the synthesis of
ligand trans- and cis-7 via the reaction of an ortho-lithiated
α-methylbenzylamine derivative with dichlorophenylphosphine.
The borane adduct was formed to prevent degradation, and the
ca. 1 : 1 product mixture was resolved by flash chromatography.
The same approach was adopted for the synthesis of the
analogous ligand 8. The ortho-lithiation and subsequent
quenching was again found to produce an inseparable 1 : 1 ratio
of diastereoisomers (Scheme 3). In contrast, using diastereo-
Scheme 1 Reagents and conditions: i) [Rh(COD)Cl]2, 1 atm H2, ligand
2 or 3.
containing one electron-rich diphosphine (2) is employed in
place of the electronically balanced donor (3).2 In the allylic
substitution reaction in Scheme 2 a product of 93% ee is
Scheme
2
Reagents and conditions: i)
CH2(CO2Me)2, BSA, NaOAc, ligand 4 or 5.
1
mol% [Pd2(dba)3],
Scheme 3 Reagents and conditions: i) nBuLi, TMEDA, PhPCl2,
BH3ؒSMe2
obtained using non-identical donor ligand 4. However, when
the ligand is replaced with a like-donor analogue 5, a dramatic
fall in asymmetric induction is observed.3
isomerically pure phosphine oxide as an intermediate,4 the
cyclisation was diastereoselective. After a simple reduction
and boration, a single diastereoisomer of trans-8 was isolated
(Scheme 4).
Scheme 4 Reagents and conditions: i) nBuLi, TMEDA, PhP(O)Cl2, ii)
Et3N, HSiCl3, BH3ؒSMe2.
As a part of a programme of ongoing investigations into new
chiral ligands containing P–N bonded architechtures,4–9 we
wished to prepare a series of enantiomerically pure dihydro-
benzazaphosphole ligands based on the general structure 6.4–7
We have also reported a synthesis of the C2-symmetric
diphosphine ligand 9. Several attempts at deprotonation to
2588
J. Chem. Soc., Perkin Trans. 1, 2001, 2588–2594
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b105495n

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incorporate the ethylene bridge between two molecules of
desilylated trans-8 were made but these consistently failed. An
alternative approach was therefore devised whereby a lithium–
bromide exchange and intramolecular cyclisation, followed
by subsequent quenching with dichlorophenylphosphine and
trapping with borane (Scheme 5), was employed.7 The final step
Scheme 6 Reagents and conditions: i) NEt3, PhPCl2, ii) BH3ؒSMe2, iii)
2 eq. tBuLi, iv) Et3N, Ph2PCl.
be trans on the basis of steric effects) and 14% of the minor
diastereoisomer (assumed to be cis) was isolated.
The pivotal step, the intramolecular cyclisation, was
attempted using ButLi at Ϫ78 ЊC. It was found to be extremely
clean and high yielding with apparent formation of a diastereo-
isomerically pure product 10 in each case. The configuration at
the phosphorus atom was not determined but according
to existing precedent, the intermolecular reaction of closely
related oxazaphospholidine–borane complexes with alkyl-
lithium reagents is known to proceed with retention of con-
figuration at phosphorus.10a–c However this is believed to arise
from a mode of attack which is cis to the P–O bond which is
unavailable to 13.10b We have therefore assumed a reaction with
inversion of configuration at phosphorus in our application, a
mode which has precedent in other systems.4 Unfortunately
numerous attempts at the phosphinylation of the free hydroxy
group, in an attempt to form trans-11, failed and only unreacted
starting material was recovered.
We suspected that the reaction had failed because the phenyl
ring adjacent to the hydroxy group was hindering the incoming
diphenylphosphine. An attempt was made to phosphinylate
benzyl alcohol and a white crystalline solid corresponding to
the product 14 was formed in 64% yield. Consequently, it was
concluded that the phenyl group was sterically preventing
phosphorylation.
Scheme 5 Reagents and conditions: i) 4.05 eq. nBuL, ii) PhPCl2, iii)
BH3ؒSMe2.
proceeded without stereoselectivity so that a statistical mixture
of trans,trans-9, cis,cis-9 and cis,trans-9 compounds was
produced. The trans,trans-9 was separated from the other
diastereoisomers in a yield of 14%.
Results and discussion
We anticipated that the cyclisation reaction depicted in Scheme
5 could be employed in the synthesis of ligands 6 through the
use of an enantiomerically pure amino alcohol. Our initial
attempted approach to the synthesis of ephedrine-derived
monodentate (10) and bidentate (11) ligands is illustrated in
Scheme 6.
The alkylation of (1S,2R)-norephedrine with 2-bromobenzyl
bromide gave a good yield (84%) of the monoalkylated
product, 12. Unfortunately the oxazaphospholidines (trans-13
and cis-13) were formed in the next step with little diastereo-
isomeric control (ca. 2 : 1). Even after repeated column chroma-
tography only 31% of the major diastereoisomer (assumed to
It seemed to us that an appropriate alternative β-amino
alcohol would be (S)-valinol. Using the same methodology as
that used for (1S,2R)-norephedrine, ligands 15 and 16 were
J. Chem. Soc., Perkin Trans. 1, 2001, 2588–2594
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Fig. 1 Pd complex of decomplexed 15 and 16 (allylic group omitted
for clarity).
Scheme 7 Reagents and conditions: i) TMEDA, PhPCl2, ii) BH3ؒSMe2,
iii) 2 eq. tBuLi, iv) Ph2PCl, v) TBDMSCl, imidazole, DMF.
Fig. 2 Pd complex of decomplexed 19 (allylic group omitted for
clarity).
both prepared successfully (Scheme 7). From the alkylation of
(S)-(ϩ)-valinol using 2-bromobenzyl bromide, using potassium
carbonate as the base, 17 was isolated in moderate yield
(58%) as a colourless oil. Fortunately, the formation of the
oxazaphospholidine, 18, proceeded selectively to give essen-
tially one diastereoisomer of product. An X-ray structure of 18
was obtained to confirm that there was a trans relationship
between the isopropyl and the phenyl groups (see Electronic
Supplementary Information†).
From the oxazaphospholidine, 18, intramolecular cyclisation
gave the monodentate ligand, 15, in a very good yield (87%).
The stereochemistry was not confirmed but again, according
to the arguments outlined above, inversion at phosphorus
was assumed to have taken place. The corresponding bidentate
ligand, 19, was made directly from the oxazaphospholidine,
18, without the isolation of 15. As predicted no hindrance
problems were encountered in the functionalisation of the
hydroxy group. Additionally, the TBDMS protected mono-
dentate ligand, 16 was made without difficulty from the corre-
sponding alcohol 15.
Changing to a more polar solvent, such as DMSO, led to
shorter reaction times but lower enantioselectivities. Solvents
such as dichloromethane or ether, were unsuitable because of
the lack of solubility of the sodium salt of dimethyl malonate.
However, using (Me3Si)2NAc (BSA) to deprotonate in situ
circumvented these difficulties to give a quantitative yield of
product, 21, in a shorter reaction time with no loss of asym-
metric induction. To avoid any possible complications, the
BSA method was adopted in all cases (Table 1).
Using the monodentate ligands 15 and 16 a number of prom-
ising results for the asymmetric allylic substitution reaction
(Scheme 8) were achieved. All the observed asymmetric induc-
tions were moderate. The highest ee of 63% (S) was achieved
using 10 mol% of ligand 15 and 2 mol% of [(C3H5)PdCl]2. The
yields were generally moderate to good. The ratio of ligand to
palladium was critical. If this fell below 2 mol% of palladium
dimer (to 10 mol% of ligand) no product was seen by TLC after
5 days, presumably because of the low concentration of active
palladium–ligand complex present.
Deborated ligand 17 was also employed in the prototype
allylic substitution reaction. The ligand derived from the
DABCO method of deboration gave a product of lower
ee (26%, R) than that from the corresponding morpholine
procedure. The highest induction of 59% (R) was obtained
using 5 mol% of the bidentate ligand and 2 mol% of palladium
dimer.
The stereochemical control may arise from an initial co-
ordination of ligands 15 and 16 to palladium to form an inter-
mediate palladium(0) species (Fig. 1). Due to their steric bulk
we believe that only one phosphorus donor ligand is present in
the complex. The other coordination site in the square planar
array will be occupied by another ligand such as a tertiary
amine (residual from the deprotection) or a chloride ion.
In the case of the diphosphine 19, we believe that it is reason-
able to assume that the ligand is acting in a bidentate manner
(Fig. 2), since the product was formed with the opposite sense
of induction. This reversal could only have arisen from a sig-
nificant change in the conformation of the ligand in the active
complex due to the presence of an additional chelating group.
It should be noted that whilst the conformations of the aryl
groups in the benzazaphosphole part of the molecule are pre-
dictable, those of the aryl rings on the other part of the ligand
are unknown.
Ligands 15 and 16 were protected from oxidation by
coordination to borane. This enabled them to be handled in the
air and purified on silica gel. Two methods for deboration were
selected which both employed the use of amines morpholine
and 1,4-diazabicyclo[2.2.2]octane (DABCO) respectively.4–7
A convenient asymmetric reaction which was selected in
order to test the efficiency of the ligands in asymmetric catalysis
is the allylic substitution of 1,3-diphenyl-3-acetoxyprop-1-ene
(20) and dimethyl malonate (Scheme 8) to give adduct 21. This
Scheme
8
Reagents and conditions: i) Y mol% [C3H5)PdCl]2,
CH2(CO2Me)2, DCM, BSA, NaOAc, X mol% deborated ligand 15, 16,
19.
reaction was selected on the basis of its widespread use as a
prototype transformation in the literature.11 Furthermore,
the simple method of calculating the enantiomeric excess by
paramagnetic shift reagent, Eu(hfc)3, was appealing.6
A number of reaction conditions were employed for the
substitution reaction with the anion of dimethyl malonate.
In summary, we have demonstrated that the intramolecular
cyclisation of a diastereoisomerically pure 1,3,2-oxazaphos-
pholidine may be used for the synthesis of dihydrobenzaza-
phosphole ligands. Such ligands may be employed in either
monodonor or bidentate form in asymmetric reactions such as
palladium-catalysed allylic substitution.
† CCDC reference number 167765. See http://www.rsc.org/suppdata/
p1/b1/b105495n/ for crystallographic files in .cif or other electronic
format.
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J. Chem. Soc., Perkin Trans. 1, 2001, 2588–2594

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Table 1 Allylic substitution reactions of 20 catalysed by Pd/15, 16 and 19 (Scheme 8)
Ligand
X (ligand mol%)
Y (Pd dimer mol%)
Deboration method
Yield/%
Ee/% (R/S)
15
15
15
15
15
15
16
16
16
19
5
10
10
10
10
10
5
10
5
5
2
4
3
2
1
1.5
2
4
2
Morpholine
Morpholine
DABCO
DABCO
DABCO
Morpholine
Morpholine
DABCO
DABCO
Morpholine
69
45
57
45
0
42 (S)
44 (S)
54 (S)
63 (S)
—
0
—
17
35
26
77
59 (R)
29 (R)
26 (R)
42 (S)
2
J 6.4, CHCH3), 2.93–3.02 (1H, m, CH3CHNH), 3.96 (2H, s,
ArCH2NH), 4.84 (1H, d, J 3.8, ArCHOH), 7.15 (1H, dt, J 7.6,
1.9, Ar-H), 7.22–7.40 (7H, m, Ar-H), 7.57 (1H, dd, J 7.6,
1.2, Ar-H); δC (100 MHz, CDCl3) 14.58 (CH3), 51.15 (CH2),
57.49 (CH), 73.03 (CH), 124.05, 125.99, 126.95, 127.44,
127.97, 128.75, 130.32, 132.85, 138.84, 141.22; m/z (CI) 321
([M(79Br)ϩ ϩ 1], 35%), 320 (100%), 214 (78).
Experimental
General
All air and moisture sensitive reactions were performed under
an atmosphere of dry nitrogen or argon in thoroughly dried
glassware. CH2Cl2 was distilled from phosphorus pentoxide.
DMF was fractionally distilled and stored over 3 Å molecular
sieves. Ether, which refers to diethyl ether, and THF were
pre-dried over sodium wire and then distilled from sodium–
benzophenone ketyl in an inert atmosphere. Petroleum ether,
which refers to the fraction boiling in the range 60–80 ЊC, was
distilled before use. Toluene was pre-dried over sodium wire
and then distilled from sodium in an inert atmosphere.
PhP(Cl)2, Ph2P(Cl) and PhP(O)Cl2 were distilled before use.
Morpholine, NEt3, pyridine and TMEDA were distilled from
CaH2. Alkyllithium reagents were titrated using the method of
Juaristi et al.12 Reactions were monitored by TLC on Whatman
aluminium backed UV254 silica gel plates. The chromatograms
were viewed under UV light and visualised using potassium
permanganate, PMA or iodine–silica. Flash column chroma-
tography was carried out under medium pressure on 60 Å silica
gel. Melting points are uncorrected. Optical rotations were
recorded on a Perkin-Elmer 141 Polarimeter and are quoted in
10Ϫ1 deg cm2 gϪ1. IR spectra were recorded on either a Perkin-
Elmer 1600 Series FT IR instrument or a Perkin-Elmer 1310FT
spectrometer. 1H NMR spectra were recorded on a Bruker
ACF250FT spectrometer at 250 MHz. 13C NMR spectra were
recorded on a JEOL JNM-GX270FT operating at 67.8 MHz,
JEOL JNM-EX400 operating at 100.4 MHz, Bruker ACF-
250FT operating at 62.9 MHz or a Bruker ACP 400 operating
(1S,2R)-2-Phenyl-3-(2-bromobenzyl)-4-methyl-5-phenyl-1,3,2-
oxazaphospholidine–borane complex 13
(1S,2R)-N-(2-Bromobenzyl)norephedrine 12 (0.30 g, 0.94
mmol) was dissolved in THF (35 cm3). At 0 ЊC triethylamine
(0.32 cm3, 2.34 mmol) and dichlorophenylphosphine (0.15 cm3,
1.13 mmol) were added dropwise. The resulting mixture was
stirred at rt for a further 2 h. At 0 ЊC borane–methyl sulfide
complex solution (0.13 cm3, 1.41 mmol) was added dropwise.
The solution was stirred at rt for a further 2 h. Saturated
sodium hydrogen carbonate solution (50 cm3) was then added.
The aqueous layer was extracted with CH2Cl2 (5 × 50 cm3). The
combined extracts were dried over sodium sulfate, filtered and
concentrated in vacuo. The resulting residue was purified by
chromatography on silica. Elution with petrol–EtOAc (10 : 1)
separated the two diastereoisomers of the product. Data for
the top spot, assigned trans-13: colourless oil (0.18 g, 43%),
bp 93–95 ЊC; [α]D20 ϩ66.9 (c 0.77, CH2Cl2); νmax(film)/cmϪ1 3061,
3031, 2977, 2929, 2871, 2385, 2279, 1437; δH (270 MHz, CDCl3)
0.2–2.2 (3H, br m, BH3), 0.64 (3H, d, J 6.6, CHCH3), 3.51–3.61
(1H, m, NCHCH3), 4.29–4.48 (2H, m, ArCH2N), 5.62 (1H, d,
J 5.7, CHCHO), 7.10 (1H, dt, J 7.6, 1.7, Ar-H), 7.23–7.32 (6H,
m, Ar-H), 7.43–7.62 (5H, m, Ar-H), 7.82–7.90 (2H, m, Ar-H);
δC (100 MHz, CDCl3) 14.82 (CH3), 52.09 (JPC 18, ArCH2N),
57.09 (JPC 15, CHN), 83.38 (JPC 4, CHO), 123.58, 123.63,
125.48, 125.72, 125.76, 125.81, 125.98, 126.05, 126.93, 127.26,
127.77, 127.90, 128.02, 128.08, 128.13, 128.23, 128.30, 128.48,
128.48, 128.57, 128.70, 128.85, 128.92, 128.97, 129.01, 129.12,
129.25, 129.60, 130.05, 130.15, 130.42, 130.51, 130.66, 130.75,
130.99, 131.11, 132.01, 132.25, 132.99, 132.54, 132.67, 134.08,
134.57, 135.69, 135.76, 136.47, 136.53, 136.60; δP (160 MHz,
CDCl3) 137.43; m/z (FABϩ) 441 ([M(79Br)ϩ ϩ 1], 15%), 346
(100%). Found: 439.083046 (Mϩ. C22H24NOBP79Br requires
439.087194). Lower spot, assigned cis-13: colourless oil (0.11 g,
27%), bp 93–96 ЊC; [α]1D8 Ϫ41.3 (c 0.32, CH2Cl2); νmax(neat)/cmϪ1
3061, 2926, 2388, 1436; δH(270 MHz, CDCl3) 0.2–1.8 (3H, br
m, BH3), 0.86 (3H, d, J 6.6, CHCH3), 3.98 (1H, septet, J 6.6,
CH3CHN), 4.26–4.48 (2H, m, ArCH2N), 5.73 (1H, d, J 5.3,
ArCHO), 7.04 (1H, dt, J 7.8, 1.7, Ar-H), 7.32–7.51 (1H, m,
Ar-H), 7.76–7.83 (2H, m, Ar-H); δC (100 MHz, CDCl3) 13.52
(CH3), 47.31 (JPC 11, ArCH2N), 59.12 (JPC 16, CHN), 84.12
(JPC 7, CHO), 124.07, 125.89, 126.03, 126.34, 126.58, 126.62,
127.62, 127.84, 128.15, 128.19, 128.28, 128.50, 128.63, 128.85,
128.92, 129.05, 129.30, 129.51, 130.86, 131.04, 131.15, 131.37,
131.50, 131.66, 132.69, 132.87, 133.05, 133.80, 134.28, 136.16,
136.22, 136.95, 137.00; δP (160 MHz, CDCl3) 135.14; m/z
(CI) 441 ([M(79Br)ϩ ϩ 1], 6%), 439 ([Mϩ ϩ 1] Ϫ H2, 5%), 426
(100%). Found: 439.085500. ([Mϩ]. C22H24NOBP79Br requires:
439.087194).
at 100.6 MHz. Both H and 13C spectra were recorded at rt.
1
DEPT techniques were commonly used to aid interpretation of
13C spectra, for which C–P couplings are quoted. In some cases
distinct P-coupled 13C peaks could not be assigned with con-
fidence and in these cases the observed peaks are listed. 31P
spectra were proton-decoupled. Mass spectra were recorded on
a VG analytical 7070E instrument. For FAB spectra, NBA was
used as a matrix. EI spectra were recorded with an ionising
potential of 70eV.
(1S,2R)-N-(2-Bromobenzyl)norephedrine 12
Potassium carbonate (1.87 g, 13.50 mmol) was added to a solu-
tion of (1S,2R)-(ϩ)-norephedrine (1.00 g, 6.61 mmol) in DMF
(30 cm3). At 0 ЊC 2-bromobenzyl bromide (1.32 g, 5.29 mmol)
was added in one portion. The solution was stirred at 0 ЊC for
60 minutes and gradually allowed to warm to rt, where it was
stirred for a further 3 h. The mixture was diluted with ether
(100 cm3). The organic layer was then washed with brine (2 ×
50 cm3), dried over sodium sulfate, filtered and concentrated in
vacuo. The resulting residue was purified by column chroma-
tography on silica. Elution with petrol–EtOAc (4 : 1) gave the
product 12 (1.42 g, 84%) as a waxy colourless oil, bp 166–168
ЊC (0.3 mmHg); [α]1D8 ϩ21.8 (c 0.79, CH2Cl2) (Found: C, 59.9; H,
5.7; N, 4.4. C16H18NOBr requires: C, 60.0; H, 5.7; N, 4.4%);
νmax(film)/cmϪ1 3404 (NH), 3061 (OH), 3028, 2968, 2926,
2870, 1668, 1492, 1468; δH (270 MHz, CDCl3) 0.86 (3H, d,
J. Chem. Soc., Perkin Trans. 1, 2001, 2588–2594
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(1S,2R)-trans-N-[(1-Methyl-2-hydroxy-2-phenyl)ethyl]dihydro-
2,1-benzazaphosphole–borane complex 10
requires: C, 74.5; H, 6.6%); νmax(Nujol)/cmϪ1 1820, 1587, 1436,
1309, 1242; δH (270 MHz, CDCl3) 0.8–1.7 (3H, br m, BH3), 5.00
(2H, d, J 6.8, ArCH2O), 7.18–7.77 (15H, m, Ar-H); δC (100
MHz, CDCl3) 68.77 (JPC 13, CH2), 127.87, 128.02, 128.13,
128.25, 128.38, 128.49, 128.57, 128.67, 128.80, 128.91, 129.00,
130.80, 130.98, 131.11, 131.24, 131.34, 131.56, 131.73, 131.89,
132.20, 136.70; m/z (CI) 307 ([Mϩ ϩ 1], 3%), 305 ([Mϩ ϩ 1] Ϫ
H2, 45%).
Oxazaphospholidine trans-13 (0.40 g, 0.91 mmol) was dissolved
in ether (30 cm3). At Ϫ78 ЊC tert-butyllithium was added drop-
wise. The mixture was stirred a further 30 minutes at Ϫ78 ЊC.
Saturated sodium hydrogen carbonate solution (50 cm3) was
added slowly. The aqueous layer was extracted with CH2Cl2 (3
× 100 cm3). The organics were combined, dried over sodium
sulfate, filtered and concentrated in vacuo. The resulting residue
was purified by chromatography on silica. Elution with petrol–
EtOAc (10 : 1) gave the product trans-10 (0.20 g, 61%) as a
white solid, mp 105–108 ЊC; [α]2D0 Ϫ246.2 (c 0.31, CH2Cl2);
νmax(CDCl3)/cmϪ1 3508, 3060, 2927, 2855, 2374, 2251; δH (270
MHz, CDCl3) 0.8–1.8 (3H, br m, BH3), 1.24 (3H, d, J 7.0,
CHCH3), 2.07 (1H, d, J 3.3, OH), 3.69–3.81 (1H, m, CH3-
CHN), 4.58 (1H, dd, J 14.3, 8.7, ArCH2N), 4.73 (1H, d, J 14.3,
ArCH2N), 4.79–4.82 (1H, m, ArCHOH), 7.21–7.65 (14H, m,
ArH); δC (67.8 MHz, CDCl3) 12.72 (CH3), 53.53 (CH2), 57.51
(JPC 10, CHN), 77.36 (JPC 7, CHO), 122.90, 125.72, 127.24,
127.89, 128.05, 128.22, 128.37, 130.76, 131.16, 131.35, 131.65,
141.99; m/z (CI) 362 ([Mϩ ϩ 1], 3%), 360 ([Mϩ ϩ 1] Ϫ H2, 38%),
240 (100%). Found: 360.168900 ([Mϩ ϩ 1] Ϫ H2. C22H24NOBP
requires 360.168849).
(S)-(؉)-2-Amino-3-methylbutan-1-ol
Sodium borohydride (6.28 g, 0.17 mol) was dissolved in THF
(200 cm3). -Valine (10.05 g, 85.47 mmol) was added in one
portion. At 0 ЊC a solution of iodine (19.50 g, 84.98 mmol)
in THF (50 cm3) was added dropwise over 50 minutes. The
mixture was gradually allowed up to rt and stirred until the
effervescence had stopped. It was refluxed for a further 24 h.
Methanol (100 cm3) was added and the solution was stirred at rt
for a further 30 minutes. The solvent was removed in vacuo. The
resulting white paste was dissolved in 20% potassium hydroxide
solution (150 cm3) and stirred for a further 24 h. The aqueous
layer was extracted with CH2Cl2 (5 × 100 cm3). The extracts
were combined, dried over sodium sulfate, concentrated in
vacuo to give an oily residue which was purified by short
path distillation [100–106 ЊC (20 mmHg)] to give the product
(4.68 g, 54%) as a colourless solid which displayed identical
physical and spectroscopic properties to an authentic sample.
Mp 30 ЊC; δH (270 MHz, CDCl3) 0.91 (3H, d, J 3.3, CH3CH),
0.93 (3H, d, J 3.3, CH3CH), 1.52–1.62 (1H, m, CH3CHCH3)
2.0–2.2 (2H, broad, NH2), 2.53–2.60 (1H, m, NH2CH), 3.30
(1H, dd, J 10.4, 8.7, CHCH2OH), 3.64 (1H, dd, J 10.4, 3.6,
CHCH2OH).
(1S,2R)-cis-N-[(1-Methyl-2-hydroxy-2-phenyl)ethyl]dihydro-
2,1-benzazaphosphole–borane complex 10
Oxazaphospholidine cis-13 (0.30 g, 0.69 mmol) was dissolved
in ether (30 cm3). At Ϫ78 ЊC tert-butyllithium was added
dropwise. The mixture was stirred for a further 30 minutes
at Ϫ78 ЊC. Saturated sodium hydrogen carbonate solution
(50 cm3) was then added slowly. The aqueous layer was
extracted with CH2Cl2 (3 × 100 cm3). The organics were com-
bined, dried over sodium sulfate, filtered and concentrated
in vacuo. The resulting residue was purified by chromatography
on silica. Elution with petrol–EtOAc (10 : 1) gave the product
cis-10 (0.20 g, 79%) as a white solid, mp 102–105 ЊC;
[α]2D0 ϩ240.3 (c 0.67, CH2Cl2); νmax(CDCl3)/cmϪ1 3507, 3061,
2982, 2937, 2905, 2849, 2374, 2244; δH (270 MHz, CDCl3)
0.8–1.8 (3H, br m, BH3), 1.01 (3H, d, J 6.8, CHCH3), 2.32 (1H,
d, J 3.4, OH), 3.56–3.64 (1H, m, CH3CHN), 4.72 (1H, dd,
J 14.7, 11.7, ArCH2N), 4.82 (1H, d, J 14.0, ArCH2N), 5.24–5.26
(1H, m, ArCHOH), 7.18–7.58 (14H, m, ArH); δC (100 MHz,
CDCl3) 11.49 (CH3), 53.11 (JPC 19, ArCH2N), 55.82 (JPC 9,
CHN), 78.59 (JPC 4, CHO), 123.58, 123.63, 125.77, 126.09,
126.32, 126.36, 127.51, 127.69, 128.17, 128.30, 128.43, 128.65,
128.76, 128.79, 128.85, 128.99, 129.05, 129.08, 131.24, 131.35,
131.48, 131.52, 131.68, 131.79, 132.03, 132.08, 142.60, 143.93,
144.01; δP (160 MHz, CDCl3) 77.58; m/z (CI) 362 ([Mϩ ϩ 1],
3%), 360 ([Mϩ ϩ 1] Ϫ H2, 47%), 240 (57%). Found 360.168900
([Mϩ ϩ 1] Ϫ H2. C22H24NOBP requires 360.168849).
(S)-2-[N-(2-Bromobenzyl)amino]-3-methylbutan-1-ol 17
2-Amino-3-methylbutan-1-ol (4.72 g, 45.79 mmol) was dis-
solved in DMF (200 cm3). Potassium carbonate (12.66 g,
91.58 mmol) was added in one portion. At 0 ЊC 2-bromobenzyl
bromide (10.64 g, 42.57 mmol) was added. The mixture was
allowed up to rt at which point it was stirred overnight. The
solution was extracted with ether (5 × 50 cm3). The extracts
were combined, dried over sodium sulfate, filtered and concen-
trated in vacuo. The oily brown residue was purified by chroma-
tography on silica. Elution with petrol–EtOAc (1 : 1) gave the
product 17 (6.76 g, 58%) as a colourless oil, bp 158 ЊC (0.3
mmHg); [α]1D7 ϩ1.4 (c 1.05, CH2Cl2) (Found: C, 52.9; H, 6.8; N,
5.1. C12H18NOBr requires: C, 53.0; H, 6.7; N, 5.1%); νmax(neat)/
cmϪ1 3356 (NH), 3063 (OH), 2957, 2872, 1568, 1468, 1440;
δH (270 MHz, CDCl3) 0.90 (3H, d, J 6.8, CHCH3), 0.96 (3H, d,
J 6.8, CHCH3), 1.85 (1H, octet, J 6.8, CH3CHCH3), 2.0–2.8
(2H, br m, NH, OH), 2.40–2.47 (3H, m, NHCHCH2), 3.39 (1H,
dd, J 10.7, 6.7, CHCH2OH), 3.65 (1H, dd, J 10.7, 4.1,
CHCH2OH), 3.85 (2H, dd, J 21.6, 13.2, ArCH2NH), 7.11 (1H,
dt, J 7.6, 1.8, Ar-H), 7.27 (1H, dt, J 6.9, 1.1, Ar-H), 7.37 (1H,
dd, J 7.5, 1.7, Ar-H), 7.53 (1H, dd, J 8.0, 1.0, Ar-H); δC (100
MHz, CDCl3) 18.42 (CH3), 19.39 (CH3), 28.72 (CH), 51.42
(CH2), 60.36 (CH2), 63.71 (CH2), 127.40, 128.65, 130.42,
132.74, 139.22; m/z (CI) 273 ([Mϩ ϩ 1], 24%), 242 ([Mϩ ϩ 1] Ϫ
CH2OH, 62%).
Benzyloxy(diphenyl)phosphine–borane complex 14
Benzyl alcohol (1.00 cm3, 8.85 mmol) was dissolved in THF
(150 cm3). At Ϫ78 ЊC n-butyllithium (5.5 cm3, 8.95 mmol)
was added dropwise. The mixture was stirred at Ϫ78 ЊC for 60
minutes and then gradually allowed up to rt and stirred for a
further 30 minutes. The temperature was lowered again to
Ϫ78 ЊC whereupon chlorodiphenylphosphine (2.4 cm3, 13.00
mmol) was added dropwise. It was stirred at Ϫ78 ЊC for 30
minutes and then warmed to rt where it was once again stirred
for 30 minutes. At Ϫ78 ЊC borane–methyl sulfide complex solu-
tion (1.3 cm3, 13.00 mmol) was added dropwise. The mixture
was gradually allowed up to rt and stirred overnight. The
mixture was concentrated in vacuo. It was diluted in toluene
(150 cm3), filtered and concentrated in vacuo. The resulting
residue was purified by chromatography on silica. Elution with
petrol–EtOAc (20 : 1) gave the product 14 (1.74 g, 64%) as a
white solid, mp 66–68 ЊC (Found: C, 74.4; H, 6.7. C19H20OPB
trans-(S)-2-Phenyl-3-(2-bromobenzyl)-4-isopropyl-1,3,2-oxaza-
phospholidine–borane complex 18†
(S)-N-(2-Bromobenzyl)valinol 17 (2.18 g, 8.05 mmol) was dis-
solved in THF (50 cm3). At rt TMEDA (2.6 cm3, 17.22 mmol)
was added dropwise. At 0 ЊC dichlorophenyl phosphine
(1.2 cm3, 8.84 mmol) was added dropwise. The solution was
stirred for a further 15 minutes at 0 ЊC and then allowed up to rt
whereupon it was stirred for a further 30 minutes. On recooling
to 0 ЊC, borane–methyl sulfide complex solution (22 cm3,
44.00 mmol) was added dropwise. The solution was gradually
2592
J. Chem. Soc., Perkin Trans. 1, 2001, 2588–2594

View Article Online
allowed up to rt where it was stirred overnight. Saturated
sodium hydrogen carbonate solution (80 cm3) was added
cautiously. The aqueous layer was extracted with CH2Cl2 (5 ×
50 cm3). The extracts were combined, dried over sodium sulfate,
filtered and concentrated in vacuo. The resulting white solid was
purified by chromatography on silica. Elution with petrol–
EtOAc (10 : 1) with 1% NEt3 gave the product 18 (2.47 g, 78%)
as a white solid, mp 96–98 ЊC; [α]1D5 ϩ85.4 (c 0.52, CH2Cl2)
(Found: C, 54.9; H, 6.2; N, 3.5. C18H24NOBPBr requires: C,
55.1 H, 6.2; N, 3.6%); νmax(Nujol mull)/cmϪ1 2384, 2338, 1588,
1568, 1438, 1395; δH (270 MHz, CDCl3) 0.2–1.8 (3H, br m,
BH3), 0.85 (3H, d, J 7.0, CHCH3), 0.90 (3H, d, J 6.8, CHCH3),
1.95–2.06 (1H, m, CH3CHCH3), 3.69 (1H, dt, J 7.3, 3.7,
CHCHN), 4.22–4.41 (4H, m, ArCH2N & CHCH2O), 7.00–7.78
(9H, m, Ar-H); δC (100 MHz, CDCl3) 14.74 (CH3), 19.31 (CH3),
27.70 (CH), 46.98 (JPC 14, ArCH2), 63.98 (CH), 67.71 (JPC 11,
CH2O), 123.27, 127.23, 128.23, 128.38, 128.88, 130.66, 130.75,
130.84, 132.08, 132.50, 136.67, 136.71; δP (160 MHz, CDCl3)
137.15; m/z (CI) 393 ([M(79Br)ϩ ϩ 1], 8%), 391([Mϩ ϩ 1] Ϫ H2,
15%) 298 (100%).
(6H, br m, BH3), 0.53 (3H, d, J 6.8, CH3), 0.84 (3H, d, J 6.8,
CH3), 1.92–2.05 (1H, m, CH3CHCH3), 3.20–3.31 (1H, m,
NCHCH2), 4.17–4.20 (2H, m, CHCH2O), 4.51–4.62 (2H, m,
ArCH2N), 7.24–7.72 (19H, m, Ar-H); δC (100 MHz, CDCl3)
19.78 (CH3), 20.34 (CH3), 28.72 (CH), 52.76 (CH2), 60.83
(CH), 67.74 (CH2), 123.03, 123.12, 128.04, 128.18, 128.33,
128.48, 128.64, 129.92, 130.70, 130.96, 131.12, 131.31, 131.43,
131.49, 131.61, 131.77, 131.90, 134.83, 135.47, 143.85, 143.96;
δP (400 MHz, CDCl3) 79.99 (d, J 63.7), 106.65 (d, J 77.1);
m/z (EI) 497 (Mϩ Ϫ BH3, 32%).
(S)-trans-N-[(1-Isopropyl-2-tert-butyldimethylsilyloxy)ethyl]-
dihydro-2,1-benzazaphosphole–borane complex 16
Benzazaphosphole 15 (0.49 g, 1.56 mmol) was dissolved in
CH2Cl2 (30 cm3). Imidazole (0.13 g, 1.86 mmol) was added at
rt and the temperature was lowered to 0 ЊC whereupon tert-
butylchlorodimethylsilane (0.28 g, 1.86 mmol) in CH2Cl2
(10 cm3) was added dropwise. The mixture was allowed to warm
to rt where it was stirred for 96 h. The reaction was quenched
with saturated ammonium chloride solution (30 cm3). The
aqueous layer was extracted with CH2Cl2 (5 × 30 cm3). The
extracts were combined, dried with sodium sulfate, filtered
and concentrated in vacuo. The resulting oil was purified by
chromatography on silica. Elution with petrol–EtOAc (20 : 1)
gave the product 16 (0.56 g, 83%) as a white solid, mp 98–100
ЊC; [α]2D1 Ϫ128.8 (c 0.52, CH2Cl2); νmax (Nujol mull)/cmϪ1 2359,
1640, 1251, 837, 782; δH (250 MHz, CDCl3) 0.14 (6H, s,
CH3SiCH3), 0.2–1.0 (3H, br m, BH3), 0.53 (3H, d, J 6.7,
CH3CHCH3), 0.92 (9H, s, C(CH3)3), 0.94 (3H, d, J 7.6,
CH3CHCH3), 2.18–2.22 (1H, m, CH3CHCH3), 2.82–2.90 (1H,
m, NCHCH), 3.95 (1H, dd, J 10.6, 3.3, CHCH2O), 4.08 (1H,
dd, J 10.6, 2.6, CHCH2O), 4.61 (1H, d, J 14.8, ArCH2N),
5.00 (1H, dd, J 14.8, 8.7, ArCH2N), 7.33–7.61 (9H, m, Ar-H);
m/z (FABϩ) 428 ([Mϩ ϩ 1], 6%), 268 (39%). Found: 427.2574
([Mϩ]. C24H39NPBOSi requires 427.2631).
(S)-trans-N-[(1-Isopropyl-2-hydroxy)ethyl]dihydrobenzaza-
phosphole–borane complex 15
Oxazaphospholidine 18 (4.03 g, 1.03 mmol) was dissolved
in ether (50 cm3). At Ϫ78 ЊC tert-butyllithium (1.21 cm3,
2.06 mmol) was added dropwise. The solution was stirred for
a further 90 minutes at Ϫ78 ЊC. Saturated sodium hydrogen
carbonate solution (100 cm3) was added. The aqueous layer was
extracted with CH2Cl2 (5 × 60 cm3). The extracts were com-
bined, dried over sodium sulfate, filtered and concentrated
in vacuo. The resulting white solid was purified by chroma-
tography on silica. Elution with petrol–EtOAc (6 : 1) with 1%
NEt3 gave the product 15 (0.28 g, 87%) as a white solid; mp
55 ЊC; [α]2D2 Ϫ206.5 (c 0.96, CH2Cl2); νmax(CDCl3)/cmϪ1 3525,
3057 (OH), 2959, 2366, 1456; δH (270 MHz, CDCl3) 0.2–1.8
(3H, br m, BH3), 0.41 (3H, d, J 6.8, CH3), 0.82 (3H, d, J 6.6,
CH3), 1.63–1.84 (1H, m, CH3CHCH3), 2.03 (1H, br s, OH),
3.07–3.19 (1H, m, CHCHN), 3.65–3.72 (1H, m, CHCH2OH),
3.83–3.89 (1H, m, CHCH2OH), 4.45–4.64 (2H, m, ArCH2N),
7.15–7.58 (9H, m, Ar-H); δC (100 MHz, CDCl3) 19.91 (CH3),
20.50 (CH3), 29.00 (CH), 51.07 (CH2), 61.58 (CH2), 62.39
(CH), 123.20, 123.30, 128.02, 128.13, 128.25, 128.30, 128.38,
128.51, 128.72, 131.18, 131.65, 131.75, 131.91, 143.78, 143.90;
δP (160 MHz, CDCl3) 79.51; m/z (CI) 314 ([Mϩ ϩ 1], 5%), 312
([Mϩ ϩ 1] Ϫ H2, 12%), 300 ([Mϩ ϩ 1] Ϫ BH3, 52%), 176 (100%).
Found: 312.168900 ([Mϩ ϩ 1] Ϫ H2. C18H24NOBP requires
312.168849).
1,3-Diphenyl-3-hydroxyprop-1-ene
Chalcone (10.24 g, 49.2 mmol) was dissolved in methanol
(100 cm3). At rt cerium() chloride heptahydrate (18.3 g,
49.2 mmol) was added in one portion. Then at 0 ЊC sodium
borohydride (2.36 g, 62.4 mmol) was added spatula-wise. After
the effervescence had ceased it was gradually allowed up to rt
where it was stirred for a further 3 h. Water (50 cm3) was added
and the aqueous layer was extracted with ether (5 × 50 cm3).
The extracts were combined, dried over magnesium sulfate,
filtered and concentrated in vacuo. The resulting oil was purified
by chromatography on silica. Elution with petrol–EtOAc (5 : 1)
gave the product (9.17 g, 89%) as a yellow oil, δH (270 MHz,
CDCl3) 2.10 (1H, s, OH), 5.39 (1H, d, J 6.2, ArCHOH), 6.38
(1H, dd, J 15.8, 6.2, CHCHCH), 6.69 (1H, d, J 15.8,
ArCHCH), 7.23–7.45 (10H, m, Ar-H).6
(S)-trans-N-[(1-Isopropyl-2-diphenylphosphanyloxy)ethyl]-
dihydro-2,1-benzazaphosphole–diborane complex 19
Oxazaphospholidine 18 (0.48 g, 1.23 mmol) was dissolved
in ether (100 cm3). At Ϫ78 ЊC tert-butyllithium (1.54 cm3,
2.46 mmol) was added dropwise. It was stirred at Ϫ78 ЊC for
30 minutes. At Ϫ78 ЊC chlorodiphenylphosphine (0.33 cm3,
1.85 mmol) was added. The mixture was gradually allowed up
to rt whereupon it was stirred overnight. At 0 ЊC borane–methyl
sulfide complex solution (0.20 cm3, 1.97 mmol) was added
dropwise. The mixture was stirred at 0 ЊC for 15 minutes and
then at rt for 30 minutes. Saturated sodium hydrogen carbonate
(100 cm3) was added. The aqueous layer was extracted with
CH2Cl2 (5 × 50 cm3). The extracts were combined, dried
over sodium sulfate, filtered and concentrated in vacuo. The
resulting yellow oil was purified by chromatography on silica.
Elution with petrol–EtOAc (20 : 1) gave the product 19 (0.23 g,
38%) as a white solid, mp 103–105 ЊC; [α]1D9 Ϫ179.7 (c 0.30,
CH2Cl2) (Found: C, 70.5; H, 7.2; N, 2.7. C30H37NOP2B2
requires: C, 70.5 H, 7.3; N, 2.7%); νmax(Nujol mull)/cmϪ1 3048,
2385, 2344, 2245, 1482, 1436; δH (270 MHz, CDCl3) 0.2–1.8
(E )-1,3-Diphenyl-3-acetoxyprop-1-ene 20
1,3-Diphenyl-3-hydroxyprop-1-ene (4.45 g, 21.15 mmol) was
dissolved in pyridine (10 cm3). DMAP (1–2 crystals, catalytic)
was added. At 0 ЊC acetic anhydride (6.0 cm3, 63.5 mmol) was
added dropwise. The solution was gradually allowed up to
rt where it was stirred overnight. Ether (200 cm3) was added and
the solution washed with saturated copper() sulfate solution
(5 × 50 cm3), saturated sodium hydrogen carbonate solution
(2 × 50 cm3) and water (2 × 25 cm3). The organic layer was dried
with magnesium sulfate, filtered and concentrated in vacuo. The
resulting yellow oil was purified by chromatography on silica.
Elution with petrol–EtOAc (20 : 1) gave the product 20 (4.55 g,
85%) as a pale yellow oil, δH (270 MHz, CDCl3) 2.10 (3H, s,
OCOCH3), 6.29–6.38 (1H, m, CHCHCH), 6.44 (1H, d, J 7.0,
ArCHOCO), 6.63 (1H, d, J 15.6, ArCHCH), 7.21–7.42 (10H,
m, Ar-H).6
J. Chem. Soc., Perkin Trans. 1, 2001, 2588–2594
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Pd catalysed allylation reaction of 20 to give 216
Acknowledgements
The procedure for deboration has been described.6 A solution
of diallylpalladium chloride dimer in dry CH2Cl2 (1 ml) was
added to the vessel containing deborated ligand. The resultant
yellow solution was refluxed for two hours, allowed to reach
room temperature and sequentially was added 1,3-diphenyl-
propenyl acetate 20 (0.2 g, 0.79 mmol, 1 eq.) dissolved in dry
CH2Cl2 (1 ml), dimethyl malonate (0.12 g, 0.87 mmol, 1.1 eq.),
bis[trimethylsilyl]acetamide (0.18 g, 0.87 mmol, 1.1 eq.), ligand
15, 16 or 19 (5 or 10 mol%) and KOAc (1 mg). The resulting
suspension was stirred at room temperature overnight, diluted
with Et2O, washed with ice-cold, saturated NH4Cl solution
(2 × 20 ml), dried with Na2SO4, filtered and concentrated under
reduced pressure. Flash chromatography (gradient elution:
5–10% EtOAc in petrol) gave the addition product 21 as a
slightly yellow oil that solidified on standing. This material gave
1H NMR data identical to that described.6 Data for 21, δH 3.50
(3H, s, CO2Me), 3.69 (3H, s, CO2Me), 3.96 (1H, d, J 11.0,
CH(CH3)2), 4.27 (1H, dd, J 8.4, 11.0, CH), 6.33 (1H, dd, J 8.4,
We thank the LINK Asymmetric Synthesis Initiative for a
studentship (to WL) and Professor D. Games and Dr B. Stein
of the EPSRC Mass Spectrometry Service at Swansea for
carrying out analyses of certain compounds. We wish to
acknowledge the use of the EPSRC’s Chemical Database
Service at Daresbury.13 MW thanks Dr A. Kawamoto for
assistance in the preparation of this paper.
References
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Synthesis, VCH Press, Berlin, 1993.
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Calculation of ee of the allylic substitution product 21
The allylation adduct (7 mg, 2.4 × 10Ϫ2 mmol) was dissolved in
chloroform-d (0.8 cm3) in a screw-top vial. (ϩ)-Eu(hfc)3 (13 mg,
1.06 × 10Ϫ2 mmol) was added and the mixture was mixed
thoroughly to give a homogeneous bright yellow solution. It
1
was then transferred into an NMR tube. The H spectrum of
the sample showed 4 sharp signals—2 singlets and a doublet—
in the region of 4 ppm. The singlets were the signals given by
each antipode for one of the methyl groups of the product. The
doublet is the non-baseline resolved signal for the other methyl
group. Therefore the integral of the doublet was identical to the
sum of the integrals of the 2 singlets. The relative integrals of
the 2 singlets were used to give the ee. Using the (ϩ)-antipode
of the shift reagent, the singlet with the highest ppm corre-
sponded to the (R)-enantiomer.
2594
J. Chem. Soc., Perkin Trans. 1, 2001, 2588–2594