Synthesis, X-ray crystal structures and Horner-Wittig addition reactions of some protected β-aminophosphine oxides

Article abstract of DOI:10.1039/b201680j

Several protected β-aminophosphine oxides have been synthesised and investigated in the Horner-Wittig addition reaction. Crystal structures of an enantiomerically pure β-amino phosphine oxide and a Horner-Wittig addition product are presented. Horner-Witt

Full text of DOI:10.1039/b201680j

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Synthesis, X-ray crystal structures and Horner–Wittig addition
reactions of some protected ꢀ-aminophosphine oxides
Neil Feeder, David J. Fox, Jonathan A. Medlock and Stuart Warren*
1
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW.
E-mail: sw134@cam.ac.uk; Fax: ϩ44 1223 336913; Tel: ϩ44 1223 336371
Received (in Cambridge, UK) 18th February 2002, Accepted 25th March 2002
First published as an Advance Article on the web 10th April 2002
Several protected β-aminophosphine oxides have been synthesised and investigated in the Horner–Wittig addition
reaction. Crystal structures of an enantiomerically pure β-amino phosphine oxide and a Horner–Wittig addition
product are presented. Horner–Wittig reactions were typically poorly stereoselective, although the ratio of
diastereoisomers can be influenced by the addition of lithium bromide.
Introduction
Results and discussion
The diphenylphosphinoyl (Ph2PO) group has been used to con-
trol relative and absolute stereochemistry and also the double
bond geometry through the Horner–Wittig reaction.1 This
methodology has been used in the synthesis of a range of
molecules with 1,42,3 and 1,54,5 related stereogenic centres
across a double bond of fixed geometry. As part of our investi-
gations into the synthetic utility of the diphenylphosphinoyl
group, we have been investigating the possible synthesis of
enantiomerically enriched allylic amines containing a double
bond of fixed geometry.
Attempts to crystallise aminophosphine oxides 3, bearing a
known stereogenic centre failed. However, the corresponding
amides (such as 4) solidify more rapidly and several different
amides were synthesised (Scheme 2, Table 1) and crystallised.
We have previously reported6,7 the synthesis of β-amino-
phosphine oxides in up to 99% ee using the asymmetric con-
jugate addition reaction developed by Davies.8 The chiral lith-
ium amide 2 adds selectively, in the presence of trimethylsilyl
chloride, to the vinylic phosphine oxides 1 giving β-amino-
phosphine oxides 3 after proto-desilylation (Scheme 1). The
Scheme 2 Reagents and conditions: i, Pd/C, H2, CH3CO2H: ii, PhCO-
Cl, pyridine, CH2Cl2.
The absolute stereochemistry of amide 4b (Ar = 4-MeOPh) was
determined from its crystal structure by the method of Flack.9
There are two molecules in the asymmetric unit (Fig. 1). Two
phenyl rings of one molecule are each disordered over two sites.
However, both molecules clearly show the stereochemistry to be
(R), as shown in Scheme 2. Having unambiguously determined
the stereochemistry of these protected β-aminophosphine
oxides, we set about investigating their reactions with aldehydes
and ketones.
We have previously investigated Horner–Wittig addition
reactions of β-amino- and β-amido phosphine oxides.10 Reac-
tion of the dilithiated derivative of the amide 5 with ketones
gave the anti diastereoisomer 6 in acceptable yield. Reaction
with an aldehyde gave a mixture of diastereoisomers 7, differing
only in the relative stereochemistry between the alcohol and
phosphorus centers (Scheme 3). We decided to investigate
Scheme 1 Reagents: i, Me3SiCl, THF, Ϫ78 ЊC; ii, 2; iii, H2O; iv, TBAF,
THF.
stereochemistry of the newly created stereogenic centre was
tentatively assigned by NMR experiments on a mandelic acid
derivative. We now confirm the stereochemistry of the con-
jugate addition reaction by X-ray crystallography, report the
rapid synthesis of racemic β-aminophosphine oxides and
the addition of their dilithiated derivatives to aldehydes and
ketones (the Horner–Wittig reaction).
Scheme 3 Reagents and conditions: i, n-BuLi, THF, LiBr, Ϫ78 ЊC then
RRЈCO: ii, NH4Cl (aq.).
whether the protecting group on nitrogen affected the diastereo-
selectivity and so we wanted to synthesise differently protected
β-aminophosphine oxides.
DOI: 10.1039/b201680j
J. Chem. Soc., Perkin Trans. 1, 2002, 1175–1180
This journal is © The Royal Society of Chemistry 2002
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Table 1 Synthesis of the amides 3 and 4
Ar
Starting material
Yield of 3 (%)6,7
Selectivity
Yield of 4 (%)
Ph
1a
1b
1c
65
76
34
98 : 2
>99 : 1
>99 : 1
50
59
–
4-MeOC6H4
2-Furyl
Fig. 1 Chem3D® representation of the two molecules (one disordered) of the amide 4b in the X-ray crystal structure.
Table 2 Effect of lithium bromide on the product ratio 14 : 15
The conjugate addition protocol described above (Scheme 1)
is an excellent method for the synthesis of enantiomerically
pure protected β-aminophosphine oxides. Its one drawback
is that high dilution is required for the conjugate addition step.
In order to investigate Horner–Wittig addition reactions we
developed a rapid synthesis of three different racemic β-amino-
phosphine oxides 10–12. Addition of lithiated methyldiphenyl-
phosphine oxide to benzonitrile gave the enamine 8 (Scheme
4). Attempted reduction with either sodium borohydride or
Amount of LiBr (eq.)
Ratio 14 : 15
0.5
2
4
1 : 0.6
1 : 0.7
1 : 1
20
1 : 1.8
1 : 4.5
Saturated solution
Scheme 5 Reagents and conditions: i, n-BuLi, THF, Ϫ78 ЊC then 13:
ii, NH4Cl (aq.).
Wittig addition could be repeated with enantiomerically pure
β-aminophosphine oxides derived from the conjugate addition
reaction (Scheme 1). Horner–Wittig addition reactions of the
amide 10 were initially difficult. The amide is insoluble in THF
at Ϫ78 ЊC and reaction at 0 ЊC produced a complex mixture of
products. Addition of lithium bromide increases the solubility
of the amide 10 and modest yields of the diastereomeric phos-
phine oxides 14 and 15 were obtained (Scheme 6). The low yield
Scheme 4 Reagents and conditions: i, n-BuLi, THF, Ϫ78 ЊC then
PhCN; ii, MeOH; iii, EtOH, Pd/C, H2; iv, CH2Cl2, Et3N, PhCOCl;
v, EtOH, Pd/C, H2, Boc2O.
lithium aluminium hydride failed, returning the enamine 8. The
reduction could be achieved by hydrogenation with palladium
on charcoal at atmospheric pressure. In fact, the amine 9 can be
formed in a one-pot procedure from methyldiphenylphosphine
oxide in sufficient purity for immediate protection. The benz-
amide 10 was synthesised in three steps in 43% yield. Direct Boc
protection of the amine 9 was found to be low yielding; good
yields could be obtained by hydrogenation of the enamine
8 in the presence of Boc anhydride. The sulfonamide 12 was
prepared in moderate yield through the addition of lithiated
methyldiphenylphosphine oxide to the imine 13 (Scheme 5).
Initially the Horner–Wittig addition was investigated with
the three protected amines 10–12. If suitable reaction con-
ditions and N-protecting group could be found, the Horner–
Scheme 6 Reagents and conditions: i, n-BuLi, THF, LiBr, Ϫ78 ЊC then
cyclohexanone: ii, NH4Cl (aq.).
may be due to competing deprotonation of cyclohexanone
as some starting material was recovered. Although the two
diastereoisomers could not be separated by column chrom-
atography, one isomer could be obtained by careful crystallis-
ation. X-Ray diffraction showed it to be the syn diastereoisomer
14 (Fig. 2). The ratio of the diastereoisomers 14 and 15 could be
influenced by the amount of lithium bromide added (Table 2).
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Fig. 3 The relationship between relative stereochemistry and 3JPH
.
diastereoselectivity of the Horner–Wittig addition reaction, the
elimination to form allylic amines was not performed.
In conclusion, although the Horner–Wittig reaction was only
poorly selective, we have developed a rapid synthesis of racemic
protected β-aminophosphine oxides. We have also confirmed
our previous tentative assignment of the stereochemistry in the
asymmetric conjugate addition reaction by X-ray crystal-
lography and obtained a crystal structure of a Horner–Wittig
addition product.
Fig. 2 Chem3D® representation of the X-ray crystal structure of the
hydroxyphosphine oxide 14.
Small amounts of lithium bromide favoured the syn isomer 14.
When THF saturated with lithium bromide was used, the reac-
tion was modestly selective for the anti isomer 15, although the
yield was low due to precipitation of lithium bromide on cool-
ing. The Horner–Wittig reaction with pivalaldehyde gave a
good yield of the hydroxyphosphine oxide 16, but three of the
four possible diastereoisomers were observed (by NMR spectro-
scopy) in a 2 : 1.3 : 1 ratio (Scheme 7). One diastereoisomer
could be isolated in low yield by chromatography.
Experimental
All solvents were distilled before use. THF was freshly distilled
from lithium aluminium hydride with triphenylmethane as the
indicator. Dichloromethane was distilled from calcium hydride
and methanol from calcium methoxide. Pyridine was dried by
stirring over and distilling from calcium hydride and was stored
over 4 Å molecular sieves. Triethylamine was dried in the same
way but stored over calcium hydride. n-Butyllithium was
titrated against diphenylacetic acid before use. All non-aqueous
reactions were carried out under argon using oven and vacuum
dried glassware. Column chromatography was performed with
Merck Kieselgel 60 (230–400 mesh). Thin layer chrom-
atography was carried out on pre-coated plates (Merck Kieselgel
60F254).
Proton and carbon NMR spectra were recorded on Bruker
DPX250, DPX400, DRX400, DRX500 Fourier Transform
spectrometers using an internal deuterium lock. Chemical
shifts are quoted in parts per million (ppm) downfield from
tetramethylsilane. The symbol “*” after a proton NMR signal
indicates that the signal disappears after a D2O shake. Carbon
NMR were recorded with broadband proton decoupling, the
symbol “ϩ” after a carbon NMR chemical shift indicates an
odd number of attached protons, whereas the symbol “Ϫ”
indicates an even number, as determined by APT or DEPT
analysis. Coupling constants for proton and carbon NMR
signals are quoted in Hz, rounded to the nearest 0.5 Hz and
are reported as observed.
Scheme 7 Reagents and conditions: i, n-BuLi, THF, LiBr, Ϫ78 ЊC then
pivalaldehyde: ii, NH4Cl (aq.).
Horner–Wittig addition reactions of the N-Boc protected
amine 11 were attempted with cyclohexanone and pivalalde-
hyde (Schemes 8 and 9). In both cases mixtures of diastereo-
Scheme 8 Reagents and conditions: i, n-BuLi, THF, LiBr, Ϫ78 ЊC then
cyclohexanone; ii, NH4Cl (aq.).
Electron Impact (EI) mass spectra were recorded on a Kratos
double focusing magnetic sector instrument using a DS503 data
system for high-resolution analysis or a MSI double focusing
magnetic sector Concept IH instrument. Electrospray (ESI)
mass spectra were recorded using a Bruker Bio-Apex II
FT-ICR instrument or a Micromass Q-Tof machine. Liquid
secondary ion mass spectra (LSIMS) were recorded on a MSI
double focusing Concept IH instrument. Microanalyses were
carried out by the staff of the University Chemical Laboratory
using a Leeman Labs CE440 Elemental Analyzer (C, H and N)
and LBK Biochrom Ultrospec 4050 (P). Melting points were
measured on a Stuart Scientific SMP1 melting point apparatus
and are uncorrected. Infra-red spectra were recorded using a
Perkin Elmer 1600 (FT-IR) spectrometer and optical rotations
were recorded on a Perkin Elmer 241 polarimeter using the
sodium D line (589 nm) at room temperature and are given in
Scheme 9 Reagents and conditions: i, n-BuLi, THF, LiBr, Ϫ78 ЊC then
pivalaldehyde; ii, NH4Cl (aq.).
isomers were obtained. The relative stereochemistry in Scheme
3
8 was assigned by comparison of the JP–CHN coupling con-
3
stants. Since our initial discovery11 that the JPH coupling
constants in β-hydroxyphosphine oxides depend on the relative
stereochemistry, all our subsequent work in this area has shown
that, within any one class of compounds, this rule is observed.
Thus with some confidence we can assign the major diastereo-
isomer 17 as the syn isomer as it has 3JP–CHN = 29 Hz, exactly the
same value as the syn diastereoisomer 14 (Fig. 3). Due to over-
lapping signals it is not possible to assign any stereochemistry
to any of the pivalaldehyde products 19. Attempts to perform
the Horner–Wittig addition on the sulfonamide 12 with
cyclohexanone or pivalaldehyde all failed. Decomposition
occurred after lithiation, even at Ϫ78 ЊC and the decomp-
osition products could not be identified. Due to the poor
units of 10Ϫ1 deg dm2 gϪ1
.
(R)-1-Benzylamido-2-diphenylphosphinoyl-1-( p-methoxyphenyl)-
ethane 4b
By the method of Bartels,7 palladium on charcoal (10%, 1.35 g,
1.2 mmol) was added to a solution of (1R,1ЈR)-N-benzyl-N-
J. Chem. Soc., Perkin Trans. 1, 2002, 1175–1180
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[1Ј-methylbenzyl]-2-diphenylphosphinoyl-1-(p-methoxyphen-
yl)ethylamine7 3b (2.23 g, 4.1 mmol) in glacial acetic acid
(35 cm3). The reaction mixture was shaken in a Parr hydrogen-
ator under hydrogen (4 atm) at 50 ЊC for 20 hours. The cooled
reaction mixture was filtered through Celite, washed with
methanol and evaporated under reduced pressure. The residue
was basified by addition of saturated sodium bicarbonate solu-
tion until the pH was greater than 8. The aqueous layer was
extracted with dichloromethane (4 × 100 cm3), the combined
organic extracts were dried (MgSO4) and evaporated under
reduced pressure. The crude free amine was used without
further purification.
(6H, m, Ph2PO and Ph), 7.33–7.17 (5H, m, Ph2PO and Ph), 4.46
(1H, td, J 10.0 and 2.5, PhCHN), 2.68 (1H, ddd, J 15.0, 11.5
and 10.0, PCHAHB), 2.57 (1H, ddd, J 15.0, 8.0 and 2.5,
PCHAHB) and 1.90* (2H, br s, NH2); δC(100 MHz; CDCl3)
146.7Ϫ (ipso-Ph), 134.7Ϫ (d, J 98.0, ipso-Ph2PO), 133.2Ϫ (d,
J 95.5, ipso-Ph2PO), 132.4ϩ (para-Ph2PO), 132.4ϩ (para-
Ph2PO), 131.6ϩ (d, J 9.0, ortho-Ph2PO), 131.2ϩ (d, J 9.5, ortho-
Ph2PO), 129.4ϩ (d, J 12.5, meta-Ph2PO), 129.3ϩ (d, J 12.0,
meta-Ph2PO), 129.3ϩ, 128.1ϩ and 126.8ϩ (Ph), 51.9ϩ (CHN)
and 40.6Ϫ (d, J 68.5, PCH2); m/z (LSIMS) 322 (100%, MHϩ),
and 289 (43, M Ϫ O Ϫ NH2) (Found: MHϩ, 322.1369.
C20H21NOP requires M, 322.1360).
The crude amine was dissolved in dry dichloromethane
(20 cm3) and cooled to 0 ЊC. Pyridine (400 µl, 4.5 mmol) and
benzoyl chloride (625 µl, 4.9 mmol) were added and the reac-
tion mixture was stirred for 2 hours. The reaction mixture was
quenched with hydrochloric acid (3 M, 30 cm3), extracted with
dichloromethane (3 × 50 cm3), dried (MgSO4) and evaporated
under reduced pressure to yield a crude product. The residue
was chromatographed (SiO2, EtOAc–hexane, 1 : 1) to give the
amide 4b (0.915 g, 49%) as needles, mp 207–208 ЊC (from
dichloromethane–hexane); Rf(EtOAc) 0.39; [α]D ϩ19.1 (c 1.0 in
CHCl3); δH(500 MHz; CDCl3) 8.91* (1H, d, J 5.5, NH), 7.98
(2H, d, J 7.5, Ph), 7.71–7.35 (13H, m, Ph), 7.17 (2H, d, J 8.0,
meta-C6H4OMe), 6.65 (2H, d, J 8.0, ortho-C6H4OMe), 5.45–
5.39 (1H, m, CHN), 3.69 (3H, s, OMe), 2.90–2.80 (2H, m,
PCH2); δC(100 MHz; CDCl3) 166.3Ϫ (CO), 158.6Ϫ (COMe),
133.9Ϫ and 133–127 (Ph and C6H4OMe), 113.8ϩ (ortho-
C6H4OMe), 55.2ϩ (OMe), 50.4ϩ (d, J 5.5, CNH), 35.9Ϫ (d,
J 67.0, PCH2); m/z (EI) 455 (82, Mϩ), 333 (87, M Ϫ NCOPh),
202 (100%, Ph2POH) (Found: Mϩ 455.1690. C28H26NO3P
requires M, 455.1650).
(RS)-1-Benzylamido-2-diphenylphosphinoyl-1-phenylethane 10
In a method analogous to that of Oh,13 n-butyllithium (2.0 M in
hexane, 12.7 cm3, 25 mmol) was added to a solution of methyl-
diphenylphosphine oxide (5 g, 23 mmol) in dry THF (100 cm3)
at 0 ЊC and the reaction mixture stirred for 30 minutes. Benzo-
nitrile (2.86 g, 2.9 cm3, 28 mmol) was added and the reaction
mixture was stirred for 30 minutes at 0 ЊC and allowed to warm
to room temperature over 1 hour. The reaction was quenched
with dry methanol (10 cm3) and the solvent removed under
reduced pressure. The residue was dissolved in absolute ethanol
(80 cm3) and palladium on charcoal (10%, 2.40 g, 2.3 mmol)
was added. The reaction mixture was vigorously stirred under a
balloon of hydrogen gas for 18 hours, filtered through Celite,
washed with ethanol and evaporated under reduced pressure to
give the crude aminophosphine oxide 9 which was used without
further purification.
The residue was dissolved in dry dichloromethane (60 cm3)
and triethylamine (4.7 g, 6.5 cm3, 46 mmol) and benzoyl chlor-
ide (4.88 g, 4.1 cm3, 35 mmol) were added. The reaction mixture
was stirred for 2 hours and quenched with water (30 cm3). The
layers were separated. The aqueous layer was extracted with
dichloromethane (3 × 30 cm3), the combined organic extracts
were washed with brine (100 cm3), dried (MgSO4) and evap-
orated under reduced pressure to give a crude product. The
residue was chromatographed (SiO2, EtOAc–hexane, 2 : 1 to
1 : 0) to give the amide 10 (4.28 g, 43%), which was spectro-
scopically identical to the enantiomerically enriched amide
reported previously.6,7
1-Amino-2-diphenylphosphinoyl-1-phenylethene 8
n-Butyllithium (1.4 M in hexane, 36.4 cm3, 51 mmol) was added
to a solution of methyldiphenylphosphine oxide (10 g, 46
mmol) in dry THF (200 cm3) at Ϫ78 ЊC and the reaction
mixture stirred for 30 minutes. Benzonitrile (5.25 g, 5.3 cm3,
51 mmol) was added and the reaction mixture was stirred for
30 minutes at Ϫ78 ЊC and allowed to warm to room tempera-
ture over 1 hour. The reaction was quenched with dry methanol
(3 cm3) and sodium borohydride (2.63 g, 69 mmol) was added in
3 portions over 15 minutes. The reaction mixture was stirred for
18 hours and was quenched by the slow addition of acetic acid
(2 cm3). Water (100 cm3) was added and the layers were separ-
ated. The aqueous layer was extracted with dichloromethane
(3 × 100 cm3). The combined organic extracts were washed with
brine (100 cm3), dried (MgSO4) and evaporated under reduced
pressure to give a crude product. The 400 MHz 1H NMR spec-
trum of this residue showed the enamine 8 as previously
reported.12
(RS)-2-(tert-Butyloxycarbonylamino)-1-diphenylphosphinoyl-2-
phenylethane 11
n-Butyllithium (2.5 M in hexane, 4.1 cm3, 10.2 mmol) was
added to a solution of methyldiphenylphosphine oxide (2 g,
9.3 mmol) in dry THF (40 cm3) at 0 ЊC and the reaction mixture
stirred for 30 minutes. Benzonitrile (1.14 g, 1.2 cm3, 11.1 mmol)
was added and the reaction mixture was stirred for 30 minutes
at 0 ЊC and allowed to warm to room temperature over 1 hour.
The reaction was quenched with dry methanol (5 cm3) and the
solvent was removed under reduced pressure. The residue was
dissolved in absolute ethanol (30 cm3) and palladium on char-
coal (10%, 980 mg, 0.92 mmol), and di-tert-butyl dicarbonate
(3.04 g, 13.9 mmol) were added. The reaction mixture was
vigorously stirred under an atmosphere of hydrogen gas for
18 hours, filtered through Celite, washed with ethanol and
evaporated under reduced pressure to give a crude product.
The residue was chromatographed (SiO2, EtOAc–hexane, 2 : 1
to 1 : 0) to give the Boc-protected amine 11 (2.55 g, 65%) as
prisms, mp 211–213 ЊC (from EtOAc–hexane); Rf(EtOAc) 0.27;
νmax(CHCl3)/cmϪ1 1708 (C᎐O), 1438 (P–Ph), 1174 (P᎐O);
(RS)-2-Amino-1-diphenylphosphinoyl-2-phenylethane 9
Palladium on charcoal (10%, 3.0 g, 2.8 mmol) was added to the
crude enamine 8 (9.1 g, approx. 28 mmol) in absolute ethanol
(100 cm3). The reaction mixture was stirred under a balloon of
hydrogen gas for 20 hours, filtered through Celite, washed with
ethanol and evaporated under reduced pressure. The residue
was dissolved in dichloromethane (100 cm3) and extracted into
hydrochloric acid (3 M, 2 × 70 cm3). The aqueous layer was
basified with sodium hydroxide pellets until the pH was greater
than 10 and extracted with dichloromethane (3 × 100 cm3). The
combined organic extracts were washed with brine (200 cm3),
dried (MgSO4) and evaporated under reduced pressure to give a
residue. The residue was chromatographed (SiO2, EtOAc–
methanol, 1 : 0 to 19 : 1) to give the aminophosphine oxide 9
(3.5 g, 39%) which has been synthesised previously, but not
isolated6,7 as an amorphous white solid; Rf(EtOAc) 0.05;
δH (400 MHz; CDCl3) 7.80–7.70 (4H, m, Ph2PO), 7.54–7.42
᎐
᎐
δH(400 MHz; CDCl3) 7.73–7.65 (2H, m, Ph2PO), 7.60–7.04
(13H, m, Ph2PO and Ph), 6.51* (1H, br s, NH), 5.03–4.93
(1H, m, CHN), 2.82–2.66 (2H, m, PCH2), 1.35 (9H, s, Me3);
δC(100 MHz; CDCl3) 155.5Ϫ (CO), 142.8Ϫ (ipso-Ph), 133.1Ϫ
(d, J 99.0, ipso-Ph2PO), 133.0Ϫ (d, J 99.0, ipso-Ph2PO), 132.6ϩ
(para-Ph2PO), 132.3ϩ (para-Ph2PO), 129.1ϩ (d, J 11.5, meta-
Ph2PO), 128.9ϩ (d, J 12.0, meta-Ph2PO), 128.8ϩ, 127.6ϩ and
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126.3ϩ (Ph), 79.7Ϫ (OCMe3), 51.8ϩ (CHN), 37.0Ϫ (d, J 68.0,
PCH2) and 28.7ϩ (CMe3); m/z (LSIMS) 422 (90%, MHϩ), 366
(38, M Ϫ CMe3), 322 (100, M Ϫ COOCMe3), 307 (50, M Ϫ
NHCOOCMe3) (Found: MHϩ, 422.1866. C25H29NO3P requires
M, 422.1885) (Found: C, 71.2; H, 6.75; N, 3.4; P, 7.4.
C25H28NO3P requires C, 71.2; H, 6.7; N, 3.3; P, 7.4%).
and 2.0, PCH), 2.43* (1H, br s, OH), 2.05–0.90 (10H, m, 5 ×
CH2); δC(125 MHz; CDCl3) 166.3Ϫ (C᎐O), 140.6Ϫ (Ph), 135.6Ϫ
᎐
(d, J 96.0, ipso-Ph2PO), 133.9Ϫ (Ph), 133.8Ϫ (d, J 94.0, ipso-
Ph2PO), 131.6ϩ (Ph), 131.4ϩ (para-Ph2PO), 130.9ϩ (d, J 9.5,
ortho-Ph2PO), 130.6ϩ (para-Ph2PO), 130.0ϩ (para-Ph2PO),
128.7ϩ (Ph), 128.4ϩ (meta-Ph2PO), 128.1ϩ (meta-Ph2PO),
128.0ϩ (Ph), 126.3ϩ (Ph), 125.8ϩ (Ph), 75.2Ϫ (COH), 55.2ϩ (d,
J 63.5, PCH), 52.5ϩ (d, J 4.5, CHN), 37.7Ϫ (d, J 5.0, CH2),
36.4Ϫ, 36.4Ϫ, 24.8Ϫ, 21.9Ϫ and 21.8Ϫ (CH2); m/z (ESI) 546
(100%, MNaϩ) (Found: MNaϩ, 546.2160. C33H34NNaO3P
requires M, 546.2174) (Found: C, 75.4; H, 6.6; N, 2.7; P, 5.9.
C33H34NO3P requires C, 75.7; H, 6.55; N, 2.7; P, 5.9%).
(RS)-1-Phenylsulfonylamido-2-diphenylphosphinoyl-1-phenyl-
ethane 12
n-Butyllithium (1.4 M in hexane, 5.5 cm3, 7.6 mmol) was added
to a stirred solution of methyldiphenylphosphine oxide (1.5 g,
6.9 mmol) in dry THF (20 cm3) at Ϫ78 ЊC. The orange solution
was stirred for 30 minutes and the N-benzylidene benzene-
sulfonamide14 13 (2.04 g, 8.3 mmol) was added. The reaction
mixture was stirred at Ϫ78 ЊC for 30 minutes and allowed to
warm to room temperature over 1 hour. The reaction was
quenched by the addition of saturated aqueous ammonium
chloride solution (20 cm3). The layers were separated and
the aqueous layer was extracted with dichloromethane (3 ×
30 cm3). The combined organic extracts were washed with brine
(50 cm3), dried (MgSO4) and evaporated under reduced pres-
sure to yield the crude β-hydroxyphosphine oxide. The residue
was chromatographed (SiO2, EtOAc–hexane, 1 : 1 to 1 : 0) to
give the phosphine oxide 12 (1.49 g, 47%) as needles, mp 220–
222 ЊC (from EtOAc–hexane); Rf(EtOAc) 0.44; νmax(solid state)/
cmϪ1 3100–3000 (br, NH), 1439 (P–Ph), 1325 (SO2), 1176 (SO2)
(1RS,2RS)-2-Benzylamido-1-diphenylphosphinoyl-1-(1Ј-
hydroxycyclohexyl)-2-phenylethane 15. Also isolated was the
hydroxyphosphine oxide 15 (40 mg, 11%) as a 2 : 1 mixture of
anti and syn isomers as a white amorphous solid.
Rf(EtOAc) 0.55; νmax(CHCl3)/cmϪ1 3500–3100 (br, OH and
HN), 1658 (C᎐O), 1438 (P–Ph), 1160 (P᎐O); δH(500 MHz;
᎐
᎐
CDCl3) 9.65* (1H, d, J 6.0, NH), 8.02–7.92 (4H, m, Ph), 7.67–
6.83 (16H, m, Ph), 6.28* (1H, br s, OH), 5.16 (1H, dd, J 14.5
and 6.0, CHN), 3.29 (1H, dd, J 10.0 and 1.5, PCH), 2.00–0.78
(10H, m, 5 × CH ); δ (125 MHz; CDCl ) 165.9Ϫ (C᎐O), 142.2Ϫ
᎐
2
C
3
(d, J 14.5, ipso-Ph), 134.9Ϫ (d, J 93.0, ipso-Ph2PO), 134.3Ϫ (ipso-
Ph), 132.3ϩ (para-Ph2PO), 132.0ϩ (para-Ph2PO), 131.4ϩ (Ph),
130.7Ϫ (d, J 98.5, ipso-Ph2PO), 130.6ϩ (d, J 9.5, ortho-Ph2PO),
129.9ϩ (d, J 8.5, ortho-Ph2PO), 129.1ϩ (d, J 11.5, meta-Ph2PO),
129.0ϩ (d, J 12.0, meta-Ph2PO), 128.6ϩ (Ph), 128.3ϩ (Ph),
127.2ϩ (Ph), 126.4ϩ (Ph), 125.3ϩ (Ph), 78.9Ϫ (d, J 3.0, COH),
53.8ϩ (CHN), 49.2ϩ (d, J 62.5, PCH), 42.1Ϫ, 40.7Ϫ, 25.9Ϫ, 21.5Ϫ
and 21.4Ϫ (CH2).
and 1151 (P᎐O); δ (400 MHz; CDCl ) 7.66 (2H, br d, J 7.0,
᎐
H
3
PhSO2N), 7.51–7.23 (13H, m, Ph and Ph2PO), 7.10–7.04 (5H,
m, PhSO2N and Ph), 4.60–4.51 (1H, m, CHN), 2.70 (1H, ddd,
J 15.5, 11.5 and 9.0, PCHAHB), 2.49 (1H, ddd, J 15.5, 8.0 and
4.0, PCHAHB), no NH peak observed; δC(100 MHz; CDCl3)
140.4Ϫ (d, J 9.5, ipso-PhCHN), 140.1Ϫ (ipso-PhSO2N), 132.1Ϫ
(d, J 100.0, ipso-Ph2PO), 132.0ϩ (Ph), 131.9ϩ (2 × para-Ph2PO),
131.1Ϫ (d, J 99.0, ipso-Ph2PO), 130.5ϩ (d, J 9.5, ortho-Ph2PO),
130.2ϩ (d, J 9.5, ortho-Ph2PO), 128.7ϩ (d, J 12.0, meta-Ph2PO),
128.6ϩ (d, J 10.5, ortho-Ph2PO), 128.5ϩ, 128.2ϩ, 127.6ϩ, 127.3ϩ
and 126.5ϩ (Ph), 54.5ϩ (d, J 4.0, CHN) and 36.7Ϫ (d, J 66.5,
PCH2); m/z (ESI) 484 (100%, MNaϩ) (Found: MNaϩ, 484.1101.
C26H24NaO3PS requires M, 484.1112) (Found: C, 67.5; H, 5.25;
N, 3.0; P, 6.7. C26H24NO3PS requires C, 67.7; H, 5.2; N, 3.0;
P, 6.7%).
1-Benzylamido-4,4-dimethyl-2-diphenylphosphinoyl-3-
hydroxy-1-phenylpentane 16. 1-Benzylamido-2-diphenylphos-
phinoyl-1-phenylethane 10 (300 mg, 0.71 mmol), n-butyllithium
(2.4 M in hexane, 620 µl, 1.5 mmol), pivalaldehyde (91 mg,
120 µl, 1.05 mmol) and lithium bromide (62 mg, 0.71 mmol)
gave a crude product that was chromatographed (SiO2,
dichloromethane–EtOAc, 2 : 1 to 1 : 1) to give one diastereo-
isomer of the hydroxyphosphine oxide 16 (52 mg, 14%) as plates,
mp 221–223 ЊC (from dichloromethane–hexane); Rf(EtOAc)
0.49; νmax(solid state)/cmϪ1 3350–3100 (br, OH and NH), 1724
(C᎐O), 1436 (P–Ph) and 1158 (P᎐O); δ (500 MHz; CDCl )
᎐
᎐
H
3
8.99* (1H, d, J 7.0, NH), 7.99–7.93 (2H, m, Ph2PO), 7.91 (2H,
br d, J 7.0, Ph), 7.85–7.80 (2H, m, Ph2PO), 7.58–7.40 (9H, m,
Ph and Ph2PO), 7.29–7.19 (4H, m, Ph), 7.14 (1H, br t, J 7.0,
para-Ph), 5.72 (1H, ddd, J 16.5, 7.0 and 1.0, CHN), 4.23–4.16
(2H, m, CHOH and OH), 3.27 (1H, br d, J 12.0, PCH) and 0.54
General procedure for Horner–Wittig additions of protected
ꢀ-aminophosphine oxides
n-Butyllithium (2.0 to 2.2 eq.) was added to a stirred solution of
the phosphine oxide (1 mmol) and dry lithium bromide (0 to
20 eq.) in dry THF (30 cm3) at Ϫ78 ЊC. The orange solution was
stirred for 30 minutes and the electrophile (1.5 eq.) was added.
The reaction mixture was stirred at Ϫ78 ЊC for one hour and
quenched by the addition of saturated aqueous ammonium
chloride solution (20 cm3). The layers were separated and the
aqueous layer was washed with dichloromethane (3 × 30 cm3).
The combined organic extracts were washed with brine (50 cm3),
dried (MgSO4) and evaporated under reduced pressure to yield
the crude β-hydroxyphosphine oxide.
(9H, s, CMe3); δC(125 MHz; CDCl3) 165.9Ϫ (C᎐O), 141.3Ϫ (d,
᎐
J 13.0, ipso-PhCHN), 134.5Ϫ (Ph), 132.4ϩ ( para-Ph2PO), 132.1ϩ
(para-Ph2PO), 131.8Ϫ (d, J 94.5, ipso-Ph2PO), 131.2ϩ (d, J 6.5,
ortho-Ph2PO), 131.1ϩ (Ph), 131.0ϩ (d, J 8.5, ortho-Ph2PO),
131.5Ϫ (d, J 96.0, ipso-Ph2PO), 129.0ϩ (d, J 12.0, meta-Ph2PO),
128.9ϩ (d, J 11.5, meta-Ph2PO), 128.5ϩ (Ph), 128.2ϩ (Ph),
127.2ϩ (Ph), 126.9ϩ (Ph), 126.8ϩ (Ph), 51.9ϩ (CHN), 44.1ϩ (d,
J 65.5, PCH), 35.8Ϫ (d, J 10.0, CMe3) and 26.5ϩ (CMe3);
m/z (ESI) 534 (100%, MNaϩ) (Found: MNaϩ, 534.2183.
C32H34NNaO3P requires M, 534.2174).
(1SR,2RS)-2-Benzylamido-1-diphenylphosphinoyl-1-(1Ј-
hydroxycyclohexyl)-2-phenylethane 14. 1-Benzylamido-2-di-
phenylphosphinoyl-1-phenylethane 10 (300 mg, 0.71 mmol),
n-butyllithium (1.9 M in hexane, 820 µl, 1.55 mmol), cyclo-
hexanone (100 mg, 110 µl, 1.06 mmol) and lithium bromide
(0.50 g, 5.7 mmol) gave a crude product that was chromato-
graphed (SiO2, EtOAc–hexane, 1 : 1) to give the hydroxyphos-
phine oxide 14 (75 mg, 20%) as needles, mp 192–194 ЊC (from
EtOAc–hexane); Rf(EtOAc) 0.55; νmax(CHCl3)/cmϪ1 3500–3100
1-Benzylamido-4,4-dimethyl-2-diphenylphosphinoyl-3-
hydroxy-1-phenylpentane 16. Also isolated was a mixture of
two more diastereoisomers of the hydroxyphosphine oxide 16
(157 mg, 44%) as a 3 : 2 mixture of diastereoisomers as a white
amorphous solid.
Rf(EtOAc) 0.67; νmax(solid state)/cmϪ1 3300–3100 (br,
OH and NH), 1660 (C᎐O), 1439 (P–Ph) and 1180 (P᎐O);
᎐
᎐
δH(400 MHz; CDCl3) 9.41 (1Hmajor, d, J 7.0, NH), 8.90 (1Hminor
d, J 6.5, NH), 8.00–6.95 (20Hmajor and 20Hminor, m, Ph2PO and
2 × Ph), 6.19 (1Hmajor, dd, J 28.0 and 6.5, CHN), 5.22 (1Hminor
,
(br, OH and HN), 1658 (C᎐O), 1438 (P–Ph), 1160 (P᎐O);
,
᎐
᎐
δH(500 MHz; CDCl3) 9.71* (1H, d, J 7.5, NH), 8.09 (2H, br dd,
J 6.5 and 1.5, Ph), 7.80–7.70 (2H, m, Ph), 7.57–6.85 (16H, m,
Ph), 6.11 (1H, dd, J 29.0 and 7.5, CHN), 3.25 (1H, dd, J 10.0
td, J 9.0 and 2.0, CHN), 3.82 (1Hminor, dd, J 23.5 and 11.0,
CHOH), 3.75 (1Hmajor, dd, J 14.5 and 4.5, CHOH), 3.33
(1Hminor, br d, J 13.5, PCH), 3.28 (1Hmajor, br d, J 5.5, PCH),
J. Chem. Soc., Perkin Trans. 1, 2002, 1175–1180
1179

View Article Online
3.13 (1Hminor, dd, J 10.5 and 2.0, OH), 0.98 (9Hmajor, s, CMe3)
(1Hb, d, J 13.5, PCH), 2.95 (1Ha, dd, J 10.5 and 0.5, PCH),
and 0.59 (9Hminor, s, CMe3). No OHmajor peak observed;
2.90–2.83 (1Hc, m, PCH), 1.42 (9Hc, s, OCMe3), 1.35 (9Hb, s,
OCMe3), 1.30 (9Ha, s, OCMe3), 0.92 (9Hb, s, CHCMe3), 0.90
(9Hc, s, CHCMe3), 0.51 (9Ha, s, CHCMe3), OH signals not
observed; δC(125 MHz; CDCl3) 155.8Ϫ (C᎐O), 155.6Ϫ (C᎐O),
δC(100 MHz; CDCl3) 166.3Ϫ
(C᎐O), 165.6Ϫ
(C᎐O),
᎐
major
᎐
minor
142.2Ϫ
(d, J 1.0, ipso-PhCHN), 140.3Ϫ
(d, J 12.5, ipso-
major
minor
PhCHN), 135–126 (m, Ph2PO and 2 × Ph), 81.3ϩmajor (d, J 4.5,
CHOH), 76.1ϩ (d, J 1.0, CHOH), 55.6ϩ
(CHN),
᎐
᎐
c
b
154.1Ϫ (C᎐O), 141.8Ϫ (ipso-Ph), 141.4Ϫ (ipso-Ph), 141.2Ϫ
᎐
minor
minor
a
c
b
a
a
a
51.9ϩmajor (d, J 5.0, CHN), 44.6ϩmajor (d, J 64.5, PCH), 41.7ϩ
(ipso-Ph), 134–125 (m, Ph2PO and Ph), 81.2ϩb (CHOH), 80.4ϩ
(CHOH), 80.4ϩ (CHOH), 79.7Ϫ (OCMe3), 78.9Ϫ
minor
(d, J 62.0, PCH), 37.1Ϫ
(d, J 11.5, CMe3), 35.9Ϫ
(d,
minor
major
c
b
ϩ
c
J 1.0, CMe3), 27.0ϩ
(CMe3) and 26.7ϩ
(CMe3); m/z
(OCMe3), 58.2ϩ (CHN), 57.5ϩ (CHN), 52.7ϩ (CHN), 45.3ϩ
major
minor
b c a c
(ESI) 534 (100%, MNaϩ) (Found: MNaϩ, 534.2161. C32H34-
(d, J 66.0, PCH), 44.9ϩ (d, J 66.5, PCH), 41.7ϩ (d, J 62.5,
b a
NNaO3P requires M, 534.2174).
PCH), 37.0Ϫa (CMe3), 37.0Ϫb (CMe3), 36.4Ϫc (CMe3), 28.4ϩ
a
ϩ
c
(OCMe3), 28.2ϩ (OCMe3), 26.9ϩ (CHCMe3), 26.5ϩ
b
b
a
Horner–Wittig addition of 2-(tert-butyloxycarbonylamino)-1-
diphenylphosphinoyl-2-phenylethane 11 to cyclohexanone
(CHCMe3) and 26.1ϩ (CHCMe3); m/z (ESI) 530 (100%,
c
MNaϩ) (Found: MNaϩ, 530.2415. C30H38NNaO4P requires M,
530.2436).
2-(tert-Butyloxycarbonylamino)-1-diphenylphosphinoyl-2-
phenylethane 11 (300 mg, 0.71 mmol), n-butyllithium (2.4 M in
hexane, 630 µl, 1.49 mmol), cyclohexanone (105 mg, 110 µl,
1.06 mmol) and lithium bromide (62 mg, 0.71 mmol) gave a
crude product that was chromatographed (SiO2, EtOAc–
dichloromethane, 1 : 1) to give a mixture (2.6 : 1) of the
hydroxyphosphine oxides 17 and 18 (112 mg, 30%) as a white
amorphous solid that we were unable to separate. Rf(EtOAc)
0.68; νmax(solid state)/cmϪ1 3500–3100 (br, OH and NH), 1666
Crystal structure determination of amide 4b
Crystal data†. C28H26NO3P,
M = 455.47, monoclinic,
a = 10.759(6), b = 10.339(6), c = 22.581(7) Å, β = 103.56(4), U =
2242(2) Å3, T = 180(2) K, space group P21, Z = 4, adsorption
coefficient 1.228 mmϪ1, 6545 reflections measured, 6122 unique
(Rint = 0.0310), which were used in all calculations. Final R
indicies [I > 2s(I )], R1 = 0.0619, wR2 = 0.1308, Flack parameter9
0.01(4).
(C᎐O), 1438 (P–Ph) and 1159 (P᎐O); m/z (ESI) 542 (100%,
᎐
᎐
MNaϩ).
Crystal structure determination of amide 14
(1SR,2RS)-2-(tert-Butyloxycarbonylamino)-1-diphenyl-
phosphinoyl-1-(1Ј-hydroxycyclohexyl)-2-phenylethane 17. δH(500
MHz; CDCl3) 7.64–7.57 (4H, m, Ph2PO), 7.35–6.68 (11H, m,
Ph2PO and Ph), 5.58 (1H, dd, J 29.0 and 8.0, CHN),
3.03 (1H, br t, J 10.5, PCH), 1.80–0.97 (10H, m, 5 × CH2), 1.31
(9H, s, CMe3). The OH and NH signals were not observed;
Crystal data†. C33H34NO3P,
M = 523.58, monoclinic,
a = 15.1746(7), b = 10.3826(5), c = 17.3450(9) Å, β = 93.820(3),
U = 2726.7(2) Å3, T = 180(2) K, space group P21/n, Z = 4,
adsorption coefficient 0.136 mmϪ1, 13304 reflections measured,
4774 unique (Rint = 0.0631), which were used in all calculations.
Final R indicies [I > 2s(I )], R1 = 0.0454, wR2 = 0.1083.
δC(125 MHz; CDCl3) 155.6Ϫ (C᎐O), 141.3Ϫ (ipso-Ph), 135.7Ϫ
᎐
(d, J 95.0, ipso-Ph2PO), 134.1Ϫ (d, J 94.5, ipso-Ph2PO), 132–125
(m, Ph2PO and Ph), 79.2Ϫ (COH), 74.9Ϫ (OCMe3), 58.8ϩ
(CHN), 53.4Ϫ (d, J 86.0, PCH), 43.7Ϫ (CH2), 36.4Ϫ (CH2), 29.5Ϫ
(CH2), 28.3ϩ (CMe3), 25.0Ϫ (CH2) and 21.8Ϫ (CH2).
Acknowledgements
We are indebted to Dr John Davies for solving one of the
crystal structures and for his assistance with the preparation of
this manuscript. We thank the EPSRC for a grant (to J. A. M.).
(1SR,2SR)-2-(tert-Butyloxycarbonylamino)-1-
diphenylphosphinoyl-1-(1Ј-hydroxycyclohexyl)-2-phenylethane
18. δH(500 MHz; CDCl3) 7.88–7.80 (2H, m, Ph2PO), 7.35–6.68
(13H, m, Ph2PO and Ph), 4.60 (dd, J 14.5 and 6.5, CHN), 3.03
(1H, br t, J 10.5, PCH), 1.80–0.97 (10H, m, 5 × CH2), 1.31 (9H,
s, CMe3). The OH and NH signals were not observed; δC(125
MHz; CDCl ) 154.2Ϫ (C᎐O), 143.3Ϫ (ipso-Ph), 135.0Ϫ (d, J 92.5,
† CCDC reference numbers 112685 and 179763. See http://www.rsc.org/
suppdata/p1/b2/b201680j/ for crystallographic files in .cif or other
electronic format.
᎐
3
References
ipso-Ph2PO), 134.1Ϫ (d, J 94.5, ipso-Ph2PO), 132–125 (m,
Ph2PO), 78.7Ϫ (COH), 71.8Ϫ (OCMe3), 55.2Ϫ (d, J 64.0, PCH),
37.3Ϫ (CH2), 35.9Ϫ (CH2), 28.9Ϫ (CH2), 28.1ϩ (CMe3), 21.4Ϫ
(CH2) and 21.3Ϫ (CH2). The peak for CHN was not observed.
1 J. Clayden and S. Warren, Angew. Chem., Int. Ed. Engl., 1996, 35,
241.
2 J. Clayden, E. W. Collington, E. Egert, A. B. McElroy and S.
Warren, J. Chem. Soc., Perkin Trans. 1, 1994, 2801.
3 J. Clayden and S. Warren, J. Chem. Soc., Perkin Trans. 1, 1994, 2811.
4 A. Nelson and S. Warren, J. Chem. Soc., Perkin Trans. 1, 1999, 1963.
5 A. Nelson and S. Warren, J. Chem. Soc., Perkin Trans. 1, 1999, 1983.
6 B. Bartels, C. G. Martin, A. Nelson, M. G. Russell and S. Warren,
Tetrahedron Lett., 1998, 39, 1637.
7 B. Bartels, J. Clayden, C. G. Martin, A. Nelson, M. G. Russell and
S. Warren, J. Chem. Soc., Perkin Trans. 1, 1999, 1807.
8 S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1991, 2,
183.
9 H. D. Flack, Acta Crystallogr., Sect. A Found. Crystallogr., 1983, 39,
876.
10 D. Cavalla, W. B. Cruse and S. Warren, J. Chem. Soc., Perkin Trans.
1, 1987, 1883.
11 A. D. Buss, W. B. Cruse, O. Kennard and S. Warren, J. Chem. Soc.,
Perkin Trans. 1, 1984, 243.
1-(tert-Butyloxycarbonylamino)-4,4-dimethyl-2-diphenyl-
phosphinoyl-3-hydroxy-1-phenylpentane 19
2-(tert-Butyloxycarbonylamino)-1-diphenylphosphinoyl-2-
phenylethane 11 (300 mg, 0.71 mmol), n-butyllithium (2.4 M
in hexane, 630 µl, 1.49 mmol), pivalaldehyde (92 mg, 117 µl,
1.07 mmol) and lithium bromide (62 mg, 0.71 mmol) gave
a crude product that was chromatographed (SiO2, EtOAc–
dichloromethane, 1 : 1) to give 3 diastereoisomers (a : b : c, 5.4 :
2.7 : 1) of the hydroxyphosphine oxide 19 (99 mg, 27%) as a
white amorphous solid that we were unable to separate; Rf-
(EtOAc) 0.67; νmax(solid state)/cmϪ1 3400–3000 (br, OH and
NH), 1716 (C᎐O), 1438 (P–Ph) and 1150 (P᎐O); δ (500 MHz;
᎐
᎐
H
12 J. Barluenga, F. López and F. Palacios, J. Chem. Res. (M), 1985,
2541.
13 W. B. Jang, W. S. Shin, K. Lee and D. Y. Oh, Synth. Commun., 1997,
27, 4101.
14 R. Albrecht, G. Kresze and B. Mlakar, Chem. Ber., 1964, 483.
CDCl3) 7.97–6.81 (15Ha, 15Hb and 15Hc, m, Ph2PO and Ph),
6.48–6.40 (1Ha, 1Hb and 1Hc, m, NH), 5.67 (1Hb, dd, J 27.0 and
8.5, CHN), 5.15 (1Hc, br d, J 25.0, CHN), 4.78 (1Ha, t, J 7.5,
CHN), 3.65 (1Ha, 1Hb and 1Hc, br d, J 14.5, CHOH), 3.23
1180
J. Chem. Soc., Perkin Trans. 1, 2002, 1175–1180