The endocyclic restriction test: Investigation of the geometries of nucleophilic substitution at phosphorus(III) and phosphorus(V)

Article abstract of DOI:10.1021/ja961375g

Double labeling has been used under the endocyclic restriction test to show that transfers of phosphorus from oxygen to carbon in the conversions of lithio phosphinite 1 to alkoxy phosphine 8, of lithio phosphinite 2 to alkoxy phosphine 9, of lithio phosphinate 3 to alkoxy phosphine oxide 10, and of lithio phosphinite borane 4 to alkoxy phosphine borane 11 proceed in an intramolecular fashion. The transfers of stereogenic phosphorus in the conversions of lithio phosphinite (R)-5 to alkoxy phosphine (R)-12, of lithio phosphinate (S)-6 to alkoxy phosphine oxide (S)-13, and of lithio phosphinite borane (R)-7 to alkoxy phosphine borane (R)-14 proceed with retention of stereochemistry at phosphorus. These results rule out the classic in-line S(N)2 pathway and the geometrically equivalent in-line addition-elimination pathway for these endocyclic transfers of phosphorus. The most likely pathway for these nucleophilic substitutions at phosphorus is initial apical nucleophilic attack followed by pseudorotation and elimination of the apical alkoxy leaving group.

Full text of DOI:10.1021/ja961375g

9052
J. Am. Chem. Soc. 1996, 118, 9052-9061
The Endocyclic Restriction Test: Investigation of the
Geometries of Nucleophilic Substitution at Phosphorus(III) and
Phosphorus(V)
Michael B. Tollefson, James J. Li, and Peter Beak*
Contribution from the Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
ReceiVed April 26, 1996X
Abstract: Double labeling has been used under the endocyclic restriction test to show that transfers of phosphorus
from oxygen to carbon in the conversions of lithio phosphinite 1 to alkoxy phosphine 8, of lithio phosphinite 2 to
alkoxy phosphine 9, of lithio phosphinate 3 to alkoxy phosphine oxide 10, and of lithio phosphinite borane 4 to
alkoxy phosphine borane 11 proceed in an intramolecular fashion. The transfers of stereogenic phosphorus in the
conversions of lithio phosphinite (R)-5 to alkoxy phosphine (R)-12, of lithio phosphinate (S)-6 to alkoxy phosphine
oxide (S)-13, and of lithio phosphinite borane (R)-7 to alkoxy phosphine borane (R)-14 proceed with retention of
stereochemistry at phosphorus. These results rule out the classic in-line SN2 pathway and the geometrically equivalent
in-line addition-elimination pathway for these endocyclic transfers of phosphorus. The most likely pathway for
these nucleophilic substitutions at phosphorus is initial apical nucleophilic attack followed by pseudorotation and
elimination of the apical alkoxy leaving group.
Introduction
interpreted to proceed through a trigonal bipyramidal intermedi-
ate which undergoes a single Berry pseudorotation to achieve
retention.7
Nucleophilic substitutions at stereogenic phosphorus(III) have
been observed to take place with inversion of configuration at
phosphorus in the majority of cases.1-3 This inversion has been
interpreted to show the reaction proceeds through a classic in-
line SN2 mechanism. A geometrically equivalent pathway is
an in-line addition-elimination mechanism in which the first
formed intermediate has the nucleophile and leaving group in
apical positions. Loss of the apical leaving group affords
inversion of configuration.1i Nucleophilic substitution at phos-
phorus(V) by carbon affords inversion of configuration in the
majority of cases.4-6 Both the in-line SN2 mechanism and the
in-line addition-elimination mechanism have been proposed.
In a few cases the hydrolysis of phosphate esters with geometries
constrained by a four-, five-, or six-membered ring have been
observed to occur with a retention of configuration and been
In the present work the endocyclic restriction test has been
used to evaluate the geometry of phosphorus transfer in the
conversions of lithio phosphinite 1 to alkoxy phosphine 8, lithio
phosphinite 2 to alkoxy phosphine 9, lithio phosphinate 3 to
alkoxy phosphine oxide 10, and lithio phosphinite borane 4 to
alkoxy phosphine borane 11.8,9 The transfers of stereogenic
phosphorus have been investigated for the conversions of lithio
phosphinite 5 to alkoxy phosphine 12, lithio phosphinate 6 to
alkoxy phosphine oxide 13, and lithio phosphinite borane 7 to
alkoxy phosphine borane 14. The results of these experiments
allow us to rule out the in-line SN2 mechanism and the in-line
addition-elimination mechanism. We suggest an addition-
pseudorotation-elimination pathway for the conversions of 1-7
to 8-14, respectively.
X Abstract published in AdVance ACS Abstracts, September 15, 1996.
(1) For examples of inversion of configuration at phosphine centers
see: (a) Smith, D. J. H.; Trippett, S. J. Chem. Soc. Chem. Commun. 1969,
855. (b) Corfield, J. R.; Oram, R. K.; Smith D. J. H.; Trippett, S. J. Chem.
Soc. Perkin Trans. 1, 1972, 713. (c) Kyba, E. P. J. Am. Chem. Soc. 1975,
97, 2554. (d) Kyba, E. P. J. Am. Chem. Soc. 1976, 98, 4805. (e) Omelanczuk,
J.; Mikolajczyk, M. J. Chem. Soc. Chem. Commun. 1976, 1025. (f)
Mikolajczyk, M.; Omelanczuk, J.; Perlikowska, W. Tetrahedron 1979, 35,
1531. (g) Mikolajczk, M. Pure Appl. Chem. 1980, 52, 959. (h) Nielsen, J.;
Dahl, O. J. Chem. Soc. Perkin Trans. 2 1984, 553. (i) Dahl. O. Tetrahedron
Lett. 1981, 22, 3281. (j) Dahl, O. Phosphorus and Sulfur 1983, 18, 201.
(2) For examples of retention of configuration in nucleophilic attack in
phosphines see: (a) Keglebich, G.; Quin, L. D. Phosphorus and Sulfur 1986,
26, 129. (b) Inch, T. D.; Hall, C. R. Tetrahedron Lett. 1976, 40, 3545.
(3) (a) Horner, J; Jordan, M. Phosphorus and Sulfur 1980, 8, 235. (b)
Mosho, J. A. Phosphorus and Sulfur 1978, 4, 273.
(4) For examples of inversion in nucleophilic attack at phosphorus(V)
see: (a) Korpiun, O.; Mislow, K. J. Am. Chem. Soc. 1967, 89, 4784. (b)
Lewis, R. A.; Mislow, K. J. Am. Chem. Soc. 1969, 91, 7009. (c) Van der
Berg, G. R.; Plantenburg, D. H. J. M.; Benschop, H. P. Recl. TraV. Chim.
1972, 91, 929. (d) Cullis, P. M.; Kaye, A. D. J. Chem. Soc. Chem. Commun.
1992, 346.
(5) For examples of retention and inversion of configuration at phos-
phorus(V) see: (a) Harrison, J. M.; Inch, T. D. J. Chem. Soc. Perkin Trans.
1 1979, 2885. (b) Haarger, M. J. P. J. Chem. Soc. Perkin Trans. 1 1977,
2057.
In the endocyclic restriction test the geometry allowed for
intramolecular transfer is restricted because the nucleophile and
leaving group are linked by a tether.9 In the conversions of 1-7
to 8-14, respectively, the carbanion and alkoxy group are
connected by varying length tethers in order to restrict the
(7) (a) Rowell, R.; Gorenstein, D. G. J. Am. Chem. Soc. 1981, 103, 5894.
(b) DeBruin, K. E.; Zon, G.; Naumann, K.; Mislow, K. J. Am. Chem. Soc.
1969, 91, 7027.
(6) (a) Westheimer, F. H. Acc. Chem Res. 1968, 1, 70. (b) Hengge, A.
C.; Edens, W. A.; Elsing, H. J. Am. Chem. Soc. 1995, 116, 5045. (c)
Macomber, R. S. J. Am. Chem. Soc. 1983, 105, 4386.
(8) Li, J; Beak, P. J. Am. Chem. Soc. 1992, 114, 9206.
(9) For a detailed review of the endocyclic restriction test, see: Beak,
P. Acc. Chem. Res. 1992, 25, 215.
S0002-7863(96)01375-3 CCC: $12.00 © 1996 American Chemical Society

The Endocyclic Restriction Test
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9053
trajectory of intramolecular endocyclic nucleophilic attack at
phosphorus. If the reaction pathway requires an in-line SN2
transition state or a geometrically equivalent in-line addition-
elimination intermediate, then the tether length needs to be
sufficiently long to allow an angle of 180° between the
nucleophile, phosphorus atom, and leaving group for intramo-
lecular transfer to observed. In the case of the transition
structure from the organolithium intermediates 1-7 intramo-
lecular nucleophilic attack through a five- or six-membered
endocyclic ring would not be possible for either in-line process
and an intermolecular reaction would be expected. If intramo-
lecular phosphorus transfer does take place a five- or six-
membered endocyclic transition state or intermediate is required,
and neither the classic in-line SN2 mechanism nor the geo-
metrically equivalent in-line addition-elimination mechanism
can be the reaction pathway. In order to determine the
molecularity of the reaction by double labeling experiments,
1-d12, 2-d12, 3-d12, and 4-d12 were prepared.
26 with retention of stereochemistry at phosphorus.14 Oxidation
of (R)-26 with m-CPBA gave phosphinate (S)-27 with a retention
of configuration at phosphorus assigned on the basis of the
established stereochemical outcome of that reaction.15
The enantiomeric ratio (er) of phosphinite (R)-26 was
determined to be 89:11 ((5%) by conversion of (R)-26 via the
Arbuzov reaction to methylphenyl-naphthylphosphine oxide
((R)-28).16 The Arbuzov reaction is known to proceed with full
retention of stereochemistry at phosphorus.1g The enantiomeric
ratio was determined by integration of the two peaks observed
by 31P NMR of a 1:1 mixture of (R)-28 and (S)-(+)-N-(3,5-
dinitrobenzoyl)-R-methylbenzylamine.17 The absolute config-
uration of (R)-28 was determined to be R by comparison of
optical rotations to known values.15 This configuration is as
expected based on the stereochemical expectations for the steps
of the synthesis.
Results
Syntheses of Phosphinite 18-d12, Phosphinate 20-d12, and
Phosphinate Borane 21-d7. Reduction of o-iodophenylacetic
acid (15) with NaBD4 and BF3‚OEt2 affords the labeled alcohol
16-d2 in good yield. Reaction with the labeled phosphinous
8
chloride 20-d10 produced doubly labeled phosphinite 18-d12.
Phosphinates 20 and 20-d12 were prepared by oxidation of
the corresponding benzyl phosphinites 19 and 19-d12 , respec-
tively, with m-CPBA in excellent yields. Phosphinite borane
21 and 21-d7 were prepared by reaction of borane with
phosphinites 19 and 19-d7.
Independent Synthesis of Phosphine Oxide (S)-33. The
configurations at phosphorus of phosphine 37, phosphine oxide
33, and phosphine borane 39 derived from (R)-26, (S)-27, and
(R)-25, respectively, were established independently by prepar-
ing phosphine oxide (S)-33. Addition of o-(methoxyethyl)-
phenyllithium to oxazaphospholidine borane (R)-23 afforded
aminophosphine borane (S)-29 as one diastereomer with reten-
tion.12 Methanolysis of (S)-29 gave phosphinite borane (R)-30
with inversion at phosphorus.13 Treatment of (R)-30 with
â-naphthyllithium gave the chiral tertiary phosphine borane (R)-
31 with inversion at phosphorus. Decomplexation of the borane
and oxidation to the phosphine oxide (S)-32 occurred with
retention of configuration at phosphorus.14,15 Finally, removal
of the methyl group with boron tribromide provided alcohol
(S)-33.
Syntheses of Chiral Phosphinite (R)-26, Phosphinate (S)-
27, and Phosphinite Borane (R)-28. The requisite chiral
phosphorus compounds were synthesized using (-)-ephedrine
as a chiral auxiliary following the work of Juge.10 Ephedrine
was first reacted with bis(N,N-diethyl)phenylphosphinous dia-
mide (22) and then complexed with borane to produce oxaza-
phospholidine borane (R)-23 as one diastereomer.11 Treatment
of (R)-24 with â-naphthyllithium yielded one diastereomer of
aminophosphine borane (S)-25 with retention of configuration
at phosphorus assigned by analogy.12 Acid catalyzed alcoholysis
of (S)-24 with o-iodophenethyl alcohol (16) produced chiral
phosphinite borane (R)-25 with inversion of stereochemistry at
phosphorus.13 Decomplexation of borane was achieved by
treatment of (R)-25 with diethylamine to afford phosphinite (R)-
(10) Juge´, S.; Stephan, M. Laffitte, J. A.; Genet, J. P. Tetrahedron Lett.
1990, 31, 6357.
(11) The configuration of (R)-19 has been established by X-ray
crystallography: Juge´, S.; Stephans, M.; Genet, J. P.; Halut-Desportes, S.;
Jeannin, S. Acta Crystallogr., Sect. C 1990, 46, 1869.
(12) The stereochemical outcome of organolithium addition to (R)-19
has been established for the methyl and o-anisyl addition products by X-ray
crystallography: Juge´, S.; Stephans, M.; Merde`s, R.; Genet, J. P.; Halut-
Desportes, S. J. Chem. Soc. Chem. Commun. 1993, 531.
(13) The methanolysis of aminophosphine boranes is reported to occur
with inversion of configuration.10

9054 J. Am. Chem. Soc., Vol. 118, No. 38, 1996
Tollefson et al.
Transfers of Phosphorus: Reactions of Phosphinite 19,
Phosphinite 18, Phosphinate 20, and Phosphinite Borane 21
with t-BuLi. Lithium-halogen exchanges of phosphinite 19,
phosphinite 18, phosphinate 20, and phosphinite borane 21
generated organolithium intermediates 1-4, respectively, which
after transfer of phosphorus from oxygen to carbon afford the
alkoxy intermediates 8-11, respectively. After addition of
water and in some cases oxidation of phosphorus, the products
were isolated and identified.
addition of tert-butyllithium at phosphorus. Phosphinate 42
arises from protonation of 3.
Previously we examined the transfer of phosphorus in the
conversion of lithio phosphinite 1 to alkoxy phosphine 8.8 The
transfer was found to afford phosphine 34 resulting from transfer
of phosphorus from organolithium 1 to alkoxide 8. Double
labeling experiments established that the transfer of phosphorus
in the conversion of 1 to 8 occurred intramolecularly.
The transfer of phosphorus in the conversion of 4 to 11 a 0.1
M solution of phosphinite borane 21 in THF was treated with
2.0 equiv tert-butyllithium. After 1 min the reaction was
quenched with methanol, and the products were isolated. Two
products observed were the phosphine borane 43 (85%) and
the phosphinite borane 44 (15%). Phosphine borane 43 arises
from the transfer of phosphorus from 4 to 11, while phosphinite
borane 44 arises from protonation of 4.
The aryllithium 2 was formed when a solution of 0.1 M
phosphinite 18 dissolved in THF was treated with 2.0 equiv of
tert-butyllithium. After 1 min the reaction was quenched with
methanol and subsequently oxidized with m-CPBA to provide
the corresponding phosphine oxides. The products observed
were (o-(2-hydroxyethyl)phenyl)diphenylphosphine oxide (38,
43%), phenethyl diphenylphosphinate (39, 41%) and tert-
butyldiphenylphosphine oxide (40, 16%). The tert-butyl addi-
tion product 40 is a result of the nucleophilic addition from
tert-butyllithium while phosphinate 39 results from protonation
of 2. The (o-(2-hydroxyethyl)phenyl)diphenylphosphine oxide
(38) which results from the transfer of phosphorus from oxygen
to carbon in the conversion of aryllithium 2 to alkoxide 9 is
the product of interest.
Transfers of Phosphorus: The Endocyclic Restriction Test
of Phosphinite 18, Phosphinate 20, and Phosphinite Borane
21. Double labeling experiments were carried out to distinguish
between the intermolecular and intramolecular pathways for the
transfer of phosphorus from oxygen to carbon. The doubly
labeled material had deuterium labels attached to the phosphorus
phenyl rings and to the tether at the phenethyl position. A
mixture of doubly labeled substrate and unlabeled substrate
would produce a statistical mixture of doubly labeled, unlabeled,
and singly labeled products from an intermolecular process while
products from an intramolecular reaction would contain only
doubly labeled and unlabeled materials.
A mixture of 18 and 18-d12 was prepared as a 0.15 M THF
solution, and its isotopic ratio was determined by FIMS (see
Table 1). The phosphinite solution of 18 and 18-d12 was treated
with 2 equiv of tert-butyllithium to give organolithium inter-
mediate 2 followed by transfer of the phosphorus atom to
provide the alkoxy phosphine 9. Treatment with water afforded
phosphine 35 as a mixture of labeled and unlabeled materials.
The isotopic composition of the product mixture as determined
by FIMS is presented in Table 1. Comparison of the isotopic
composition of 35 with the expected isotopic compositions for
intramolecular and intermolecular processes establishes that the
transfer of phosphorus in the conversion of phosphinite 18 to
phosphine 35 occurs in an intramolecular fashion. Intermo-
lecular products were <5% as indicated by the d2 and d10
isotopic composition of the product 35.
The transfer of phosphorus in the conversion of lithio
phosphinate 3 to alkoxy phosphine oxide 10 was examined by
a double labeling experiment in order to compare the transfer
of phosphorus(V) to phosphorus(III). A mixture of 20 and 20-
d12 was prepared as a 0.01 M THF solution and its isotopic
ratio was determined by FABMS (see Table 2). Treatment of
the phosphinate mixture of 20 and 20-d12 with 2 equiv of tert-
The transfer of phosphorus in the conversion of 3 to 10 was
carried out when a 0.1 M solution of phosphinate 20 in THF
was treated with 2.0 equiv of tert-butyllithium. After 1 min
the reaction was quenched with water, and the products were
isolated. The products observed were phosphine oxide 41
(85%), phenethyl diphenylphosphinate 42 (8%), tert-butyldiphe-
nylphosphine oxide (40, 2%), and phosphinate 20 (5%).
Triarylphosphine oxide 41 arises from transfer of phosphorus
from oxygen to oxygen in the conversion of organolithium 3
to alkoxide 10. The tert-butylphosphine oxide 40 results from
(14) Imamoto, T.; Kusumoto, T.; Suzuki, N.; Sato, K. J. Am. Chem. Soc.
1985, 107, 5301.
(15) Skowronska, A. Bull. De L'Academie Polanaise Des Sciences 1973,
21, 459.
(16) Korpiun, O.; Lewis, R. A.; Chickos, J.; Mislow, K. J. Am. Chem.
Soc. 1968, 90, 4842.
(17) Dunach, E.; Kagen, H. B. Tetrahedron Lett. 1985, 26, 2649.

The Endocyclic Restriction Test
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9055
Table 1. Isotopic Ratios for Phosphine Mixture 35 from the
Double Label Experiment Using Phosphinite Mixture 18a
Table 3. Isotopic Ratios for Phosphine Oxide Mixture 41 from the
Double Label Experiment using Phosphinite Borane Mixture 21a
M
M + 1 M + 2 M + 10 M + 11 M + 12
M
M + 1 M + 2 M + 5 M + 6 M + 7
reactant 18b
product 35
54
58
1
0
1
5
0
5
0
1
3
1
8
4
8
4
35
28
35
15
reactant 21b
product 41c
55
52
0
0
0
6
0
1
0
0
1
0
10
8
10
5
34
35
34
14
intramolecularc 54
intermolecularc 30
intramoleculard 55
intermoleculard 33
19
24
19
24
a Determined by FIMS (error (5%). b A mixture of 18 and 18-d12
with minor amounts of 18-d11. c Calculated based on the isotopic ratios
of the starting materials.
a Determined by FABMS (error (5%). b A mixture of 21 and 21-d7
with minor amounts of 21-d6. Only one phenyl ring was labeled.
c Phosphine borane 43 was converted to phosphine oxide 41. d Calcu-
lated based on isotopic ratio of 21 and 21-d7.
butyllithium produced organolithium 3 as a precursor to alkoxy
phosphine oxide 10 which upon treatment with water afforded
phosphine oxide 41. The product mixture was analyzed by
FABMS as presented in Table 2. Comparison of experimentally
observed values with the calculated isotopic compositions for
intramolecular and intermolecular reactions show the transfer
of phosphorus(V) in the conversion of 3 to 10 occurred in an
intramolecular fashion.
Table 2. Isotopic Ratios for Phosphine Oxide Mixture 41 from the
Double Label Experiment using Phosphinate Mixture 20a
M
M + 1 M + 2 M + 10 M + 11 M + 12
reactant 20b
product 41
47
41
0
0
0
4
0
4
0
2
0
2
9
16
9
41
42
41
22
Transfers of Stereogenic Phosphorus: Reaction of Phos-
phinite (R)-26, Phosphinate (S)-27, and Phosphinite Borane
(R)-25 with t-BuLi. In order to determine the stereochemical
course of the endocyclic nucleophilic substitutions at phosphorus
the transfers of phosphorus from oxygen to carbon were
examined for the conversions of (R)-5, (S)-6, (R)-7-(R)-12, (S)-
13, and (R)-14, respectively. A 0.1 M solution of phosphinite
(R)-26 in THF was treated with 2 equiv of tert-butyllithium at
-78 °C to afford organolithium (R)-5. Rearrangement of (R)-5
afforded alkoxy phosphine (R)-12. After 1 min the solution
was treated with water to afford phosphine (R)-45 which was
oxidized with 30% hydrogen peroxide. The oxidation proceeds
with retention of configuration to give phosphine oxide (S)-
33.18,19 The enantiomeric ratio of (S)-33 was determined to be
94:6 ((5%) by analysis of its acetate derivative (S)-46 by chiral
stationary phase (CSP) HPLC while the er for (R)-26 was
determined to be 89:11 ((5%).
intramolecularc 47
intermolecularc 24
20
25
5
a Determined by FABMS (error (5%). b A mixture of 20 and 20-
d12 with minor amounts of 20-d10 and 22-d11 materials c Calculated
based on the isotopic ratios of the starting materials.
The molecularity of the transfer of a borane complexed
phosphorus atom in the conversion of lithio phosphinite borane
4 to alkoxy phosphine borane 11 was also investigated by a
double label experiment. A mixture of 21 and 21-d7 was
prepared as a 0.10 M THF solution and its isotopic composition
determined by FABMS (Table 3). The solution was treated
with 2 equiv of tert-butyllithium to produce organolithium 4 as
a precursor to alkoxide 11 which upon treatment with water
afforded phosphinite borane 43. In order to provide a reliable
deuterium analysis phosphinite borane 43 was converted to
phosphine oxide 41 by treatment of 43 with diethylamine
followed by oxidation with m-CPBA. The isotopic composition
of the product mixture was analyzed by FABMS as shown in
Table 3. Comparison of the observed isotopic ratio with the
expected isotopic distribution for an intramolecular and inter-
molecular reaction establishes that the transfer of phosphorus
in the conversion of 21 to 43 occurs in an intramolecular fashion.
The configuration of (S)-33 was determined by comparing
the product to independently synthesized (S)-33 by CSP HPLC

9056 J. Am. Chem. Soc., Vol. 118, No. 38, 1996
Tollefson et al.
and CD spectroscopy. The S configuration at phosphorus in
the transfer of phosphorus establishes the conversion of (R)-5
to (R)-12 proceeds with an overall retention of stereochemistry.
The stereochemistry for the transfer of a stereogenic phos-
phorus(V) atom in the conversion of (S)-6 to phosphine oxide
13 was investigated with phosphinate (S)-27. Phosphinate (S)-
27 with an er of 94:6 was treated with 2 equiv of tert-
butyllithium in THF at -78 °C to provide lithio phosphine oxide
(S)-6. Rearrangement of (S)-6 afforded alkoxy phosphine oxide
(S)-13. After 1 min the reaction was treated with water, and
phosphine oxide (S)-33 was isolated. The enantiomeric ratio
of (S)-33 was determined to be 96:4 by analysis of its acetate
derivative (S)-46 by CSP HPLC. This result establishes that
the transfer of chiral phosphorus(V) in the conversion of (S)-6
to (S)-13 occurs with an overall retention of stereochemistry at
phosphorus.
Four possible addition-elimination pathways are illustrated
for the reaction of (R)-5. (1) Addition of the aryl nucleophile
may occur such that the nucleophile is located in an apical
position, while the leaving group is in an equatorial position.
This intermediate is shown by the trigonal bipyramidal anion
48.21 Direct elimination of the equatorial alkoxy leaving group
from intermediate 48 would give a product with a retention of
stereochemistry. (2) Addition of the aryl nucleophile could
occur at an equatorial position with the leaving group axial,
shown as phosphorane 49. Direct loss of the apical alkoxy
group from 49 would also afford a product with retention of
stereochemistry. (3) An alternative addition of the nucleophile
at an equatorial position could occur with the leaving group in
a equatorial position, illustrated by intermediate 50.22 Direct
loss of the equatorial alkoxy group from 50 would lead to an
inversion of stereochemistry. (4) A final possibility involves
Berry pseudorotation between phosphoranes 48 and 49.23 This
allows for reorganization around phosphorus in such a manner
that two equatorial ligands are exchanged with two apical
ligands, while one equatorial ligand remains equatorial as a pivot
ligand. This pathway allows either an apical addition-pseu-
dorotation-apical elimination pathway or equatorial addition-
pseudorotation-equatorial elimination pathway in addition to
more complex pseudorotation pathways. In the endocyclic case
apical addition would afford phosphorane 48 followed by
pseudorotation to afford phosphorane 49 in which the alkoxy
leaving group could depart from the apical position to give
retention of configuration. Pathways 1, 2, and 4 all afford the
product with a retention of configuration, while pathway 3 yields
inversion.
The transfer of a stereogenic phosphorus atom complexed to
borane was examined for the conversion of lithio phosphinite
borane (R)-7 to alkoxy phosphine borane 14 using phosphinite
borane (R)-25. Phosphinite borane (R)-25 with an er of 94:6
was treated with 2 equiv of tert-butyllithium lithio phosphinite
borane (R)-7 which led to the alkoxy phosphine borane (R)-14.
After 1 min water was added, and phosphine borane (R)-47 was
isolated. The enantiomeric ratio of (R)-47 was determined to
be 92:8 by analysis of the acetate derivative (S)-46 prepared by
decomplexation of borane, oxidation, and acylation of (R)-47.
The transfer of phosphorus in the conversion of (R)-7 to (R)-14
occurs with an overall retention of stereochemistry at phospho-
rus.
The present work established that the stereochemistry of the
endocyclic transfers of phosphorus proceeds with retention of
configuration for the conversions of phosphinite (R)-5 to
phosphine (R)-12, phosphinate (S)-6 to phosphine oxide (S)-
13, and phosphinite borane (R)-7 to phosphine borane (R)-14.
On this basis pathway 3 can be ruled out.
Equatorial addition followed by apical elimination or apical
addition followed by equatorial elimiation has been suggested
and cannot be excluded on the present experimental data.24,25
However, Mislow suggests that if the bond making or breaking
step is rate determining, then apical addition and elimination
will be more favorable than equatorial addition and elimina-
tion.25 Based on the assumption that the bond making and
breaking process is rate determining, the general interpretation
for nucleophilic substitutions which involve trigonal bipyramidal
intermediates is that addition of the nucleophile occurs at the
apical position and elimination of the leaving group occurs from
the apical position.25,26 When those restrictions are applied to
the present cases pathways 1 and 2 can be eliminated. Mech-
anisms which require pseudorotation to occur following pathway
4 require futher consideration.
Discussion
The intramolecular conversions of phosphinite 1 to phosphine
8, phosphinite 2 to phosphine 9, phosphinate 3 to phosphine
oxide 10, and phosphinite borane 4 to phosphine borane 11
establish that transfer of phosphorus can occur within either a
five- or six-membered endocyclic ring. These results which
establish that a 180° angle between the nucleophilic, phosphorus
atom, and leaving group is not required for nucleophilic
substitution at phosphorus rule out the in-line SN2 and in-line
addition-elimination mechanism for these transfers.20 The
reaction pathways which are consistent with an oblique angle
for phosphorus transfer involve addition-elimination sequences.
(20) The endocyclic restriction test was attempted for a 15- and
18-membered endocyclic ring; however, only intermolecular t-butyl addition
at phosphorus was observed.
(21) Only one apical addition is shown, but an equivalent apical addition
could occur to afford the naphthyl group and nucleophile in apical positions.
(22) An intermediate similar to 41 has been observed by NMR: Ross.
M. R.; Martin, J. C. J. Am. Chem. Soc. 1981, 103, 1234.
(23) Berry, R. S. J. Chem. Phys. 1960, 32, 933.
(24) () (a) Corriu, R. J. P.; Guerin, C. In AdVances in Organometallic
Chemistry; Stone, F. G. A., West, R., Eds.; Academic Press: New York,
1982; p 265. (b) Corriu, R. J. P.; Guerin, C. J. Organomet. Chem. 1980,
198, 231.
(25) Mislow, K. Acc. Chem. Res. 1970, 3, 321.
(26) (a) Sheldrick, W. S.; Schmidpeter, A.; Zwaschka, F.; Dillon, K. B.;
Platt, A. W. G.; Waddington, T. C. J. Chem. Soc., Dalton Trans. 1981,
413. (b) Lattman, M.; Olmstead, M. M.; Power, P. P.; Rankin, D. W. H.;
Robertson, H. E. Inorg. Chem. 1988, 27, 3012.
(18) Horner, L. Pure Appl. Chem. 1964, 5, 225.
(19) Other oxidants (m-CPBA and t-BuOOH) also provide retention of
sterochemistry and gave similar results.

The Endocyclic Restriction Test
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9057
Figure 1. Desargues-Levi diagram.
A Desargues-Levi diagram25 (Figure 1) illustrates all of the
possible pseudorotations for the intermediates in the reaction
of (R)-5. In this diagram each ligand is assigned a number: 1
) alkoxy leaving group, 2 ) aryl nucleophile, 3 ) b-naphthyl,
4 ) phenyl, and 5 ) lone pair. The two apical substituents in
the trigonal bipyramid are denoted in ascending numerical order
for the symbols used at each vertex on the diagram. If the
equatorial substituents increase in assigned value in a counter-
clockwise direction when the trigonal bipyramid is viewed down
the apical bonds with the lowest priority apical ligand in back,
a bar is placed above the symbol i.e. 2h4h. This nomenclature is
illustrated in Figure 1 for phosphorane 2h4h. If the equatorial
substituents increase in assigned value in a clockwise direction
then no bar is used i.e. 24. Intermediates 12 and O1h2h are not
shown due to the 180° requirement for the apical-apical
placement of the nucleophile and leaving group for intermediate
12 and 1h2h is not energetically preferred. Each intermediate
trigonal bipyramidal anion has two or three possible pseudoro-
tation pathways available to it as indicated by the lines
connecting vertices in the diagram. Also indicated on the
diagram is the overall stereochemistry of the product resulting
from loss of the alkoxide from the TBP intermediate. The
intermediates from the top half would result in a retention of
configuration while the bottom half leads to inversion.
the possible pseudorotations from equatorial addition intermedi-
ate 50 3h4h should not be on the reaction pathway because any
pseudorotation from intermediate 50 3h4h would involve the
energetically unfavorable placement of the lone pair of electrons
in an apical position.
Under the above assumptions the only possible addition-
pseudorotation-elimination pathway which is consistent with
the data is (R)-5 to 48 2h4h to 49 (13) to (R)-12. Apical addition
of the aryl group to phosphorus gives the trigonal bipyramidal
intermediate 48 2h4h. Pseudorotation of 48 2h4h to 49 (13)
reorganizes the bonds about phosphorus such that the leaving
group can become apical while maintaining the lone pair in an
equatorial position. Loss of the alkoxy leaving group from 49
(13) leads to (R)-12 with a retention of stereochemistry at
phosphorus. This process can be generalized for transfer of
phosphorus(V) and borane complexed to phosphorus for the
endocyclic phosphorus systems investigated in this work. In
the cases of intermediates 3, 4, 6, and 7 the oxygen or borane
anion is required to always remain in the equatorial position.
If the lone pair of electrons is assumed to always occupy an
equatorial position a single pathway can be specified for these
reactions. The assumption that no pseudorotation can lead to
an intermediate containing a lone pair of electrons at the apical
position is supported by VSEPR theory,27 MO calculations28
and the qualitative considerations of s character.29 In this case
any vertex with a 5 (lone pair) is considered not to be accessible.
The only allowed pseudorotations on this energy profile are
between intermediates 2h4h (48) and 13(49) and between inter-
mediates 2h3h and 14. All other pseudorotations from these
phosphorane intermediates would require placing the lone pair
of electrons at the energetically unfavorable apical position.
Indeed, if the lone pair could be apical, then racemization
would be expected, for example, 2h4h (48) to 15 would afford
inversion. However, in all of the endocyclic cases only retention
of configuration with no racemization is observed. Pathway 3
has been eliminated based on the observed retention. In addition
The calculations of Bachrach and Mulhearn27 for the reaction
of hydride with phosphine are consistent with the assigned
mechanism. The addition of hydride at phosphine is calculated
to occur at an apical position to form a C2V phosphorane anion
as a discrete intermediate. Pseudorotation is calculated to occur
through a C4V transition state with the lone pair of electrons
always in an equatorial position. Placement of the lone pair of
electrons at an apical position was calculated to be 30.33 kcal/
mol higher in energy than the C2V phosphorane with the lone
pair equatorial. Attempts to find the C1 transition state structure
leading to an apical lone pair of electrons were unsuccessful in
the calculations.
(27) Gillespie, R. J.; Hargittai, I. The VSEPR Model of Molecular
Geometry; Allyn and Bacon: New York, 1991.
(28) Bachrach, S. M.; Mulhearn, D. C. J. Chem. Phys. 1993, 97, 12229.
(29) Bent, H. Chem. ReV. 1961, 61, 275.
(30) Bondarenko, N. A.; Tsvetkov, E. N.; Matrozov, E. I.; Kabachnik,
M. I. IzV. Akad. Nauk SSR, Ser. Khim. 1978, 2109.
(31) Korpiun, O.; Lewis, R. A.; Chickos, J.; Mislow, K. J. Am. Chem.
Soc. 1968, 90, 4842.
Precedent for the proposed pathways exists.7,26 Retention of
configuration at phosphorus has been observed in the hydrolysis

9058 J. Am. Chem. Soc., Vol. 118, No. 38, 1996
Tollefson et al.
of constrained phosphate triesters and of phophetanes.7 In each
of those cases the leaving group and nucleophile were unable
to both occupy apical position simultaneously.
2-o-Iodophenethyl Alcohol-(r,r)-d2 (16-d2). A solution of 2.0 g
(7.63 mmol) of o-iodophenylacetic acid in 5.9 mL THF was cooled in
an ice bath to 0 °C. To the solution was added 550 mg (13.14 mmol)
of sodium borodeuteride. A solution of 1.2 mL (9.60 mmol) of boron
trifluoride etherate in 2.3 mL of THF was added dropwise to the
o-iodophenylacetic acid solution at 0 °C. The solution was warmed
to room temperature and stirred overnight. The reaction mixture was
quenched with saturated sodium carbonate solution. The resulting
mixture was extracted twice with benzene. The combined organics
were washed with 5% NaOH solution and saturated sodium chloride
solution and dried over sodium sulfate. The solvent was removed in
vacuo and further purification by vacuum distillation at 156 °C/5 Torr
yielded 1.41 g (74%) of 2-o-iodophenethyl alcohol-d2 (16-d2). 1H NMR
(300 MHz) δ 1.92 (br s, 1H, OH), 2.98 (s, 2H), 6.86-6.92 (m, 1H),
7.24-7.35 (m, 2H), 7.81 (d, J ) 7.82 Hz, 1H). 13C NMR (75 MHz)
δ 43.40, 61.64 (m), 100.74, 128.23, 128.26, 130.26, 139.53, 140.98.
EIMS m/z 250.
(o-Iodophenethyl-d2) Di(phenyl-d5)phosphinite (18-d12). To a
solution of 500 mg (2.0 mmol) of o-iodophenethyl alcohol-d2 (16-d2)
in 13 mL of THF cooled to -20 °C in a ice salt bath was added 1.33
mL of diisopropylethylamine and 380 mL of diphenylphosphinous
chloride-d10 (17-d10). The solution was stirred 30 min at -20 °C. The
amine hydrochloride was removed by vacuum filtration, and the THF
was removed in vacuo. The resulting mixture was chromatographed
on neutral alumina (20% EtOAc in hexane) to yield 526 mg (59%) of
18-d12 as a colorless oil. 1H NMR (400 MHz) δ 3.10 (s, 2H), 6.83-
6.88 (m, 1H), 7.18-7.19 (m, 2H), 7.77 (d, J ) 7.81 Hz). 13C NMR
(100 MHz) δ 42.28 (d, J ) 8.6 Hz), 68.35 (m), 100.73, 127.65 (t, J )
24.4 Hz)), 127.72 (t, J ) 24.0 Hz), 128.12, 128.17, 128.92 (t, J )
24.0 Hz), 129.77 (t, J ) 23.7 Hz), 130.00 (t J ) 23.3 Hz), 130.36,
130.44, 140.71, 141.44 (d, J ) 17.6 Hz). 31P NMR (162 MHz) δ
113.21. FIMS m/z 317 (M - I). d12, 84%; d11, 12%.
O-(o-Iodobenzyl) Diphenylphosphinate (20). To a solution of 200
mg (0.48 mmol) 18 in 20 mL ethyl acetate was added 150 mg (0.74
mmol) m-CPBA and the solution was stirred 30 min then washed with
saturated aqueous Na2CO3 and brine. The solution was dried over
sodium sulfate, and filtered, and the solvent evaporated in vacuo. The
residue was purified by MPLC (30% EtOAc in hexane) to yield 187
mg (90%) of 20 as a white solid. Mp ) 62-63 °C. 1H NMR (300
MHz) δ 5.07 (d, J ) 6.7 Hz, 2H), 6.98 (t, J ) 7.5 Hz, 1H), 7.31 (t, J
) 7.7 Hz, 1H), 7.37-7.54 (m, 7H), 7.78-7.89 (m, 5H). 13C NMR
(125MHz) δ 69.89 (d, J ) 5.0 Hz), 97.45, 128.29, 128.49 (d, J ) 12.5
Hz), 129.05, 129.71, 130.50, 131.60 (d, J ) 10 Hz), 132.22, 138.65
(d, J ) 7.5 Hz), 139.21. 31P NMR (121 MHz) δ 33.16. FABMS m/z
435 (M + H)+. Anal. Calcd for C19H16IO2P: C, 52.56; H, 3.71.
Found: C, 52.75; H, 3.74.
The present endocyclic reactions which proceed with retention
at phosphorus are different from the acyclic cases where
inversion of stereochemistry is observed.1,4 This difference
illustrates the fact that this endocyclic restriction test is
permissive in the sense that an endocyclic reaction may proceed
via a different pathway than an unconstrained reaction. The
endocyclic test indicates what nucleophilic trajectories are
possible and cannot by itself rule out geometries not tested. The
in-line SN2 pathway and in-line addition-elimination pathway
is unavailable in the endocyclic systems due to the restriction
of the tether. It is possible that the endocyclic system is related
to the acyclic system and both proceed through a TBP
intermediate in an addition-elimination mechanism. In the
acyclic reaction apical addition of the nucleophile can occur
opposite the leaving group allowing direct apical loss of the
leaving group leading to an inversion of configuration. How-
ever, in the endocyclic cases the leaving group is not properly
situated in an apical position after apical attack of the nucleo-
phile therefore pseudorotation must occur after apical addition
in order to allow apical elimination of the alkoxy group.
Conclusion
The transfer of phosphorus in the conversions of lithio
phosphinite 1 to alkoxy phosphine 8, of lithio phosphinite 2 to
alkoxy phosphine 9, of lithio phosphinate 3 to alkoxy phosphine
oxide 10, and of lithio phosphinite borane 4 to alkoxy phosphine
borane 11 can occur in an intramolecular endocyclic fashion.
These results ruled out the in-line SN2 and in-line addition-
elimination mechanisms in these cases. The observed retention
of stereochemistry at phosphorus for the transfer of stereogenic
phosphorus in the conversions of lithio phosphinite 5 to alkoxy
phosphine 12, of lithio phosphinate 6 to alkoxy phosphine oxide
13, and of lithio phosphinite borane 7 to alkoxy phosphine
borane 14 differs from the observed inversion of configuration
in acyclic reactions. The endocyclic transfers of phosphorus
are proposed to follow an addition-pseudorotation-elimination
pathways shown for 48 to 49, 51 to 53, and 52 to 54. In these
reactions apical addition of the nucleophile is followed by
pseudorotation of the trigonal bipyramidal intermediate and
apical loss of the leaving group to give retention of stereo-
chemistry at phosphorus.
O-(o-Iodobenzyl-d2) Di(phenyl-d5)phosphinate (20-d12). Labeled
phosphinite 20-d12 was prepared in a manner analogous to 20 above in
80% yield. 31P NMR (121 MHz) δ 33.16.
O-o-Iodobenzyl Diphenylphosphinite Borane (21). To a solution
of 2.0 g (8.54 mmol) of o-iodobenzyl alcohol, 5.0 mL of (28.70 mmol)
diisopropylethylamine and 50 mL of THF cooled to 0 °C was added
1.8 mL (10.02 mmol) of diphenylphosphinous chloride, and the solution
was stirred 30 min at 0 °C. The amine hydrochloride salt was filtered,
and the THF was removed in vacuo. The resulting oil was dissolved
in 50 mL of toluene, and 2.0 mL (20.0 mmol) of 10 M borane-dimethyl
sulfide complex was added. The solution was stirred 3 days, and the
solvent was removed in vacuo. The resulting oil was purified by
chromatography on silica (10% EtOAc in hexane) to yield a white solid.
Recrystallization of the solid (methanol) yielded 1.49 g (40%) of O-o-
iodobenzyl diphenylphosphinite borane (21). Mp 79-80 °C. 31P NMR
(162 MHz) δ 107.5 (q, J ) 76 Hz). 1H NMR (400 MHz) δ 0.6-1.6
(m, 3H), 4.89 (d, J ) 6.6 Hz, 2H), 6.81-6.85 (m, 1H), 7.14-7.18 (m,
1H), 7.27-7.37 (m, 7H), 7.63-7.68 (m, 5H). 13C NMR (100 MHz) δ
72.30, 97.60, 128.17, 128.47 (d, J ) 10.7 Hz), 129.08, 131.08 (d, J )
11.4 Hz), 131.64, 131.82 (d, J ) 2.3 Hz), 138.68 (d, J ) 8.4 Hz),
139.08. FABMS m/z 103(29), 119(59), 121(13), 135(35), 149(12), 152-
(30), 153(17), 154(11), 155(38), 201(31), 203(15), 217(39), 291(32),
303(13), 419(29), 430(11), 431(39). Anal. Calcd for C19H19BIOP: C,
52.82; H, 4.43. Found: C, 53.20; H, 4.56.
Experimental Section
General Methods. All reagents were obtained from commercial
sources and used without further purification unless stated otherwise.
Diethyl ether (Et2O) and tetrahydrofuran (THF) were dried and distilled
over sodium and acetophenone. Hexanes were distilled prior to use.
See supporting information.
2-(o-Iodophenethyl) Diphenylphosphinite (18). To a solution of
420 mg (1.73 mmol) of o-iodophenethyl alcohol in 11.2 mL of THF
cooled to -20 °C in an ice salt bath were added 1.14 mL (6.54 mmol)
of diisopropylethylamine and 415 mL of chlorodiphenylphosphine. The
solution was stirred 30 min at -20 °C. The amine hydrochloride was
removed via vacuum filtration, and the THF was removed in vacuo.
The resulting mixture was chromatographed on a neutral alumina (20%
EtOAc in hexane) to yield 614 mg (82%) of 2-(o-iodophenethyl)
diphenylphosphinite as a colorless oil. 1H NMR (400 MHz) δ 3.12 (t,
J ) 7.08 Hz, 2H), 4.00-4.12 (m, 2H), 6.86-6.91 (m, 1H), 7.31-7.46
(m, 12 H), 7.79 (d, J ) 7.81 Hz). 13C NMR (100 MHz) δ 42.44 (d,
J ) 7.6 Hz), 68.83 (d, J ) 19.1 Hz), 100.73, 128.13, 128.18, 128.25,
129.21, 130.32 (d, J ) 22.1 Hz), 130.47, 139.38, 140.73, 141.66 (d, J
) 18.3 Hz). 31P NMR (162 MHz) δ 113.42. FIMS m/z 305 (M - I).
Anal. Calcd for C20H18IOP: C, 55.58; H, 4.20. Found: C, 55.82; H,
4.23.
O-o-Iodobenzyl Diphenylphosphinite Borane-d7 (21-d7). To a
solution of 375 mg (1.59 mmol) of o-iodobenzyl alcohol-d2, 825 µL

The Endocyclic Restriction Test
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9059
(4.77 mmol) of diisopropylethyl amine, and 10.6 mL of THF cooled
to 0 °C was added 360 mg (1.60 mmol) of diphenylphosphinous
chloride-d5 (17-d5). The solution was stirred 1 h at 0 °C. The
precipitate was filtered, and the solvent was removed in vacuo. The
oil was dissolved in 11 mL of toluene, and 300 µL of BH3‚SMe2 was
added. The solution was stirred 3 days, and the solvent was removed
in vacuo. The residue was purified by flash chromatography on silica
(10% EtOAc in hexane) followed by HPLC (10% EtOAc in hexane)
to yield 138 mg (20%) 21-d7. 31P NMR (162 MHz) δ 107.55 (q, J )
79 Hz). 1H NMR (400 MHz) δ 0.7-1.7 (m, 3H), 6.99-7.084 (m,
9H). Isotopic analysis (EIMS) 50% d7, 41% d6, 8% d5, 1% d4.
(R)-O-(2-(o-Iodophenyl)ethyl) (2-Naphthyl)phenylphosphinite Bo-
rane ((R)-25). To a solution of 5.19 g (12.56 mmol) of aminophosphine
borane (S)-24 in 5 mL of THF was added 13.59 mL (54.78 mmol) of
o-iodophenethyl alcohol and 700 µL (12.60 mmol) 18 M sulfuric acid.
The resulting reaction mixture was stirred 16 h. Ether was added to
the reaction mixture, and it was washed with 10% aqueous H2SO4
solution. The extracts were dried over sodium sulfate, filtered, and
solvent evaporated in vacuo. The resulting residue was purified by
flash chromatography on silica (10% EtOAc in hexane) to yield 1.51
g (24%) of (R)-25 as a colorless oil. 31P NMR (162 MHz) δ 105.6
(m). 1H NMR (400 MHz) δ 0.6-1.6 (m, 3H), 3.06 (t, J ) 6.8 Hz,
2H), 4.08-4.14 (m, 2H), 6.77-6.82 (m, 1H), 7.11-7.14 (m, 2H), 7.27-
7.49 (m, 6H), 7.56-7.61 (m, 2H), 7.70-7.77 (m, 4H), 8.19 (d, J )
12.7 Hz, 1H). 13C NMR (100 MHz) δ 41.65 (d, J ) 6.8 Hz), 66.23
(d, J ) 2.3 Hz), 125.80 (d, J ) 9.9 Hz), 126.81, 127.70, 128.12, 128.22,
128.37, 128.47, 128.49, 128.60,129.11, 130.57, 131.11 (d, J ) 11.5
Hz), 131.76 (d, J ) 2.3 Hz), 131.80 (d, J ) 64.1 Hz), 132.33 (d, J )
12.2 Hz), 134.54 (d, J ) 1.5 Hz), 139.45, 139.98. Anal. Calcd for
was purified by flash chromatography on silica (10-30% EtOAc in
hexane) to yield 2.16 g (57%) of (S)-29 as a white solid. Mp ) 97-
98 °C. 31P NMR (162 MHz) δ 70.89 (m). 1H NMR (400 MHz) δ
0.5-1.6 (m, 3H), 1.24 (d, J ) 7.1 Hz, 3H), 1.84 (br s, 1H), 2.63 (d, J
) 7.6 Hz, 3H), 2.91-3.02 (m, 2H), 3.27 (s, 3H), 3.54-3.58 (m, 2H),
4.29-4.34 (m, 1H), 4.95 (d, J ) 3.7 Hz, 1H), 7.21-7.32 (m, 5H),
7.38-7.49 (m, 7H), 7.55-7.60 (m, 2H). 13C NMR (100 MHz) δ 11.45
(d, J ) 4.6 Hz), 31.59 (d, J ) 3.0 Hz), 33.83 (d, J ) 4.6 Hz), 58.04
(d, J ) 9.9 Hz), 58.48, 72.99, 79.02 (d, J ) 1.6 Hz), 125.95, 126.07
(d, J ) 9.2 Hz), 127.41, 128.28, 128.46 (d, J ) 9.9 Hz), 128.68, 130.80
(d, J ) 2.3 Hz), 130.97 (d, J ) 1.5 Hz), 131.29 (d, J ) 9.2 Hz), 131.78
(d, J ) 9.9 Hz), 132.25, 132.86, 132.94 (d, J ) 8.3 Hz), 142.53. Anal.
Calcd for C25H33BNO2P: C, 71.27; H, 7.89; N, 3.32. Found: C, 71.03;
H, 7.96; N, 3.44.
(R)-O-Methyl (o-(methoxyethyl)phenyl)phenylphosphine Borane
((R)-30). To a solution of 2.16 g (5.13 mmol) of aminophosphine
borane (S)-29 in 50 mL of methanol was added 285 µL of 18 M sulfuric
acid, and the resulting mixture was stirred overnight. To the solution
was added saturated aqueous sodium carbonate solution, and the
methanol was removed in vacuo. The solution was ether extracted,
dried over sodium sulfate, and filtered, and the solvent was removed
in vacuo. The residue was purified by flash chromatography on silica
(10% EtOAc in hexane) to yield 950 mg (64%) of (R)-30 as a colorless
oil. 31P NMR (162 MHz) δ 110.0 (m). 1H NMR (400 MHz) δ 0.6-
1.6 (m, 3H), 2.82 (t, J ) 7.3 Hz, 2H), 3.06 (s, 3H), 3.11 (dt, J ) 7.3,
1.7 Hz, 2H), 3.63 (d, J ) 12.2 Hz, 3H), 7.20-7.24 (m,2H), 7.52-7.57
(m, 4H), 7.75-7.80 (m, 1H). 13C NMR (100 MHz) δ 33.76 (d, J )
4.6 Hz), 53.89 (d, J ) 2.3 Hz), 58.31, 72.51, 126.18 (d, J ) 11.4 Hz),
128.57 (d, J ) 10.6 Hz), 129.38 (d, J ) 59.5 Hz), 131.04 (d, J ) 10.6
Hz), 131.21 (d, J ) 8.4 Hz), 131.69 (d, J ) 2.3 Hz), 132.15 (d, J )
2.2 Hz), 132.23 (d, J ) 64.1 Hz), 133.57 (d, J ) 15.2 Hz), 142.43 (d,
J ) 8.4 Hz). Anal. Calcd for C16H22BO2P: C, 66.70; H, 7.69, H.
Found: C, 66.31; H, 7.85.
(R)-((o-Methoxyethyl)phenyl)(â-naphthyl)phenylphosphine Bo-
rane ((R)-31). To a solution of 1.35 g (6.52 mmol) of â-bromonaph-
thalene in 16 mL of THF cooled to -78 °C was added 9.3 mL (13.02
mmol) of 1.4 M tert-butyllithium, and the solution was stirred 5 min
at -78 °C. The resulting naphthyllithium solution was added to a
solution of 940 mg (3.26 mmol) of phosphinite borane (R)-30 in 16
mL of THF at -78 °C. The reaction mixture was stirred for 1 h while
warming to 0 °C and an additional hour at room temperature. The
reaction was quenched with water, and the THF was removed in vacuo.
The residue was dissolved in ether, washed with saturated aqueous NaCl
solution, dried over sodium sulfate, and filtered, and solvent removed
in vacuo. The residue was purified by flash chromatography on silica
(5% EtOAc in hexane) and recrystallized with dichloromethane and
hexane to yield 354 mg (28%) of phosphine borane (R)-31 as a colorless
oil. 31P NMR (162 MHz) δ 21.1 (m). 1H NMR (400 MHz) δ 0.7-
1.8 (m, 3H), 2.89 (dt, J ) 2.5, 6.7 Hz, 2H), 3.05 (s, 3H), 3.28 (dt, J )
3.4, 7.1 Hz, 2H), 6.98-7.01 (m, 1H), 7.09-7.11 (m, 1H), 7.37-7.60
(m, 10H), 7.76-7.83 (m, 3H), 8.10 (d, J ) 13.0 Hz, 1H). 13C NMR
(100 MHz) δ 34.62 (d, J ) 6.1 Hz), 58.30, 72.55, 126.23 (d, J ) 58.0
Hz), 126.38 (d, J ) 9.1 Hz), 126.88, 127.55, 127.76, 128.08, 128.16
(d, J ) 4.6 Hz), 128.55 (d, J ) 9.2 Hz), 128.76, 128.83, 128.94, 129.40
(d, J ) 58.0 Hz), 131.27 (d, J ) 2.2 Hz), 131.38, 131.47, 132.75 (d,
J ) 9.4 Hz), 133.25 (d, J ) 9.2 Hz), 134.25 (d, J ) 1.5 Hz), 134.55
(d, J ) 8.4 Hz), 143.87 (d, J ) 10.7 Hz). [R]D ) +81.7(0.7° (c 0.63,
CDCl3). Anal. Calcd for C25H26BOP: C, 78.15; H, 6.82. Found: C,
78.15; H, 6.76.
(S)-((o-Methoxyethyl)phenyl)(â-naphthyl)phenylphosphine Oxide
((S)-32). A solution of 24 mg (0.06 mmol) of phosphine borane (R)-
31 and 1.0 mL of diethylamine was heated at reflux for 1 h. The
diethylamine was removed in vacuo. The residue was dissolved in
1.0 mL of ether, and 20 mg (0.06 mmol) of m-CPBA was added. The
solution was stirred 0.5 h followed by washing with 10% aqueous
NaOH solution. The extracts were dried over sodium sulfate and
filtered, and the solvent was removed in vacuo to yield 24 mg (100%)
of phosphine oxide (S)-32 as a colorless oil. 31P NMR (162 MHz) δ
32.41. 1H NMR (400 MHz) δ 3.16 (s, 3H), 3.18-3.22 (m, 2H), 3.48
(t, J ) 6.4 Hz, 2H), 7.10-7.16 (m, 2H), 7.44-7.60 (m, 8H), 7.67-
7.72 (m, 2H), 7.86-7.92 (m, 3H), 8.28 (d, J ) 14.0 Hz, 1H). 13C
NMR (100 MHz) δ 34.42 (d, J ) 4.6 Hz), 58.23, 72.68, 125.63 (d, J
C24H23BIOP: C, 58.10; H, 4.67. Found: C, 58.27; H, 4.86. [R]D
+12.5(0.2° (c 2.51, CDCl3).
)
(R)-O-(2-(o-Iodophenyl)ethyl) (2-Naphthyl)phenylphosphinite ((R)-
26). A solution of 1.51 g (3.04 mmol) of phosphinite borane (R)-25
in 25 mL of diethylamine was heated at reflux for 2 h. The amine
was removed in vacuo and purified by flash chromatography on neutral
alumina (10% EtOAc in hexane) to yield 1.47 g (100%) of phosphinite
(R)-26 as a colorless oil. 31P NMR (162 MHz) δ 113.89 (m). 1H NMR
(400 MHz) δ 3.39 (t, J ) 7.0 Hz, 2H), 4.33 (dt, J ) 9.0, 7.0 Hz, 2H),
7.07-7.13 (m, 1H), 7.40-7.78 (m, 9H), 7.98-8.17 (m, 5H), 8.27 (d,
J ) 8.8 Hz). 13C NMR (400 MHz) δ 42.49 (d, J ) 7.8 Hz), 68.91 (d,
J ) 18.3 Hz), 125.75, 126.21, 126.29, 126.37, 126.59, 126.70, 127.62,
127.70, 127.81, 127.91 (d, J ) 6.0 Hz), 128.13, 128.20, 128.26, 128.29,
129.23, 130.27, 130.53 (d, J ) 3.4 Hz), 131.20 (d, J ) 28.3 Hz), 133.74,
139.43. [R]D ) +23.5 ( 0.7° (c 0.56, CDCl3).
(S)-O-(2-(o-Iodophenyl)ethyl) (2-Naphthyl)phenylphosphinate ((S)-
27). To a solution of 207 mg (0.43 mmol) of phosphinite (R)-26 in 4
mL of THF was added 135 mg of 55% m-CPBA and was stirred for 1
h. Ether was added to the solution and was washed with 5% aqueous
NaOH solution, 5% aqueous HCl solution, and brine. The extracts
were dried over magnesium sulfate, filtered, and solvent evaporated in
vacuo. The residue was purified by MPLC (50% EtOAc in hexane)
to yield 142 mg (66%) of phosphinate (S)-27 as a colorless oil. 31P
NMR (162 MHz) δ 32.73. 1H NMR (400 MHz) δ 3.21 (t, J ) 6.8 Hz,
2H), 4.24-4.30 (m, 2H), 6.91-6.95 (m, 1H), 7.26-7.29 (m, 2H), 7.39-
7.43 (m, 2H), 7.47-7.65 (m, 4H), 7.73-7.90 (m, 6H), 8.38 (d, J )
14.2 Hz, 1H). 13C NMR (100 MHz) δ 41.47 (d, J ) 7.7 Hz), 63.81
(d, J ) 6.1 Hz), 100.58, 126.21 (d, J ) 11.4 Hz), 126.79, 127.36,
127.70, 128.19, 128.24, 128.29, 128.42, 128.55, 128.91, 130.66, 131.15
(d, J ) 138 Hz), 131.50, 131.60, 132.12 (d, J ) 3.1 Hz), 132.30 (d, J
) 14.5 Hz), 134.73 (d, J ) 2.3 Hz), 139.51, 139.96. Anal. Calcd for
C24H20IO2P: C, 57.85; H, 4.04. Found: C, 57.94; H, 4.43.
(S)-(N-((1R,2S)-2-Hydroxy-1-methyl-2-phenylethyl)-N-methyl)-
amino((o-methoxyethyl)phenyl)phenylphosphine Borane ((S)-29). To
a solution of 1.95 g (9.07 mmol) of o-bromo(methoxyethyl)benzene
in 10 mL of ether cooled to -78 °C was added 13.95 mL (18.14 mmol)
of 1.3 M tert-butyllithium, and the solution was stirred 5 min at -78
°C. The resulting organolithium solution was added dropwise to a
solution of 2.60 g (9.12 mmol) of oxazaphospholidine borane (R)-23
in 5 mL of THF and 15 mL of ether cooled to -78 °C, stirred 0.5 h at
-78 °C, warmed to room temperature, and stirred 1 h. The reaction
mixture was quenched with water, ether extracted, dried over sodium
sulfate, and filtered, and the solvent was removed in vacuo. The residue

9060 J. Am. Chem. Soc., Vol. 118, No. 38, 1996
Tollefson et al.
) 12.2 Hz), 126.76, 126.87, 127.76, 128.14, 128.27, 128.52 (d, J )
12.2 Hz), 128.90, 130.06 (d, J ) 103.8 Hz), 130.95 (d, J ) 103.0 Hz),
131.47, 131.81 (d, J ) 5.3 Hz), 131.94, 132.01 (d, J ) 2.3 Hz), 132.40
(d, J ) 13.7 Hz), 133.03 (d, J ) 103.8 Hz), 133.04 (d, J ) 103.8 Hz),
133.65, 133.65 (d, J ) 13.0 Hz), 134.55 (d, J ) 2.2 Hz), 144.27 (d, J
) 7.0 Hz).
(S)-((o-Hydroxyethyl)phenyl)(â-naphthyl)phenylphosphine Oxide
((S)-33). To a solution of 25.8 mg (0.07 mmol) of (S)-32 in 1 mL of
dichloromethane cooled to -78 °C was added 12 µL (0.13 mmol) of
boron tribromide. The solution was stirred for 45 min. Saturated
aqueous sodium bicarbonate was added, extracted, and washed with
brine. The extract was dried over magnesium sulfate and filtered, and
the solvent removed in vacuo to yield 1.8 mg (7%) (S)-33 as a colorless
oil. 31P NMR (162 MHz) δ 35.91. 1H NMR (400 MHz) δ 3.07-3.10
(m, 2H), 3.92-3.94 (m, 2H), 6.95-7.01 (m, 1H), 7.15-7.20 (m, 1H),
7.44-7.62 (m, 10H), 7.86-7.92 (m, 3H), 8.20 (d, J ) 13.4 Hz, 1H).
This spetral data is identical to (S)-33 prepared below.
Diphenyl o-(Methoxyethyl)phenylphosphine Oxide. To a solution
of 1.26 g (5.84 mmol) of 1-bromo-2-methoxyethylbenzene in 1.05 mL
of THF cooled to -78 °C was added 8.35 mL (11.69 mmol) of 1.4 M
t-butyllithium. After 30 min 1.05 mL (5.84 mmol) of diphenylphos-
phinous chloride was added dropwise, and the solution was stirred 30
min at -78 °C and an additional 30 min at room temperature. To the
reaction mixture was added 1.80 g (5.95 mmol) of m-CPBA and stirred
30 min at room temperature. Ether was added, the solution was washed
with saturated aqueous Na2CO3 solution and brine, dried over magne-
sium sulfate and filtered, and the solvent evaporated. The residue was
purified by flash chromatography on silica (50-100% EtOAc in hexane)
to yield 923 mg (47%) ether as a colorless oil. 31P NMR (162 MHz)
δ 32.19. 1H NMR (400 MHz) δ 1.18 (t, J ) 6.9 Hz, 2H), 3.17 (s,
3H), 3.44 (t, J ) 6.6 Hz, 2H), 7.00-7.07 (m, 1H), 7.11-7.17 (m, 1H),
7.42-7.66 (m, 11H), 7.88-7.92 (m, 1H).
Diphenyl (o-(2-Hydroxyethyl)phenyl)phosphine Oxide (37). To
a solution of 923 mg (2.74 mmol) of diphenyl o-(methoxyethyl)-
phenylphosphine oxide in 3 mL of CH2Cl2 at -78 °C was added a
solution of 650 µL (6.88 mmol) of BBr3 in 3 mL of CH2Cl2 dropwise,
and the solution was stirred 2 h while warming to 0 °C. Water was
added, the solution was washed with saturated aqueous NaHCO3
solution and brine, dried over sodium sulfate, and filtered, and the
solvent evaporated. Upon standing the colorless oil solidified. Mp )
166-168 °C (lit.29 168-169 °C). 31P NMR (162 MHz) δ 35.92. 1H
NMR (400 MHz) δ 3.07 (t, J ) 5.6 Hz, 2H), 3.91 (t, J ) 5.6 Hz, 2H),
4.95 (br s, 1H), 6.91-6.97 (m, 1H), 7.14-7.18 (m, 1H), 7.41-7.62
(m, 12H).
156 mg (0.350 mmol) of 2-(2-iodophenyl)ethyl) diphenylphosphinite-
d12 (18-d12) in 5.2 mL of THF was cooled to -78 oC. An aliquot was
taken for mass spectral analysis. Another solution of 905 mL (0.923
o
mmol) of tert-butyllithium (1.0 M in pentane) was cooled to -78 C
and then added to the phosphinite solution. After 1 min the reaction
mixture was quenched with saturated aqueous sodium bisulfite solution.
Dichloromethane was added, and the mixture was extracted with brine.
The resulting mixture was dried over sodium sulfate and filtered, and
the solvent was removed in vacuo to yield a yellow oil. The oil was
purified by MPLC (silica gel, 30% EtOAc in hexane) to yield 36 mg
(16%) of 35 as a colorless oil. 31P NMR (161 MHz) δ -14.68, -15.13.
For isotopic analysis see Table 1.
Preparation of Phosphine Oxide 41. To a solution of 200 mg
(0.48 mmol) of 19 in 4 mL of THF cooled to -78 °C was added 1.0
mL (1.0 mmol) of 1 M tert-butyllithium and was stirred 10 min at
-78 °C. The reaction mixture was quenched with saturated aqueous
Na2CO3, and ethyl acetate was added. The organic layer was separated,
washed with brine, dried over Na2SO4, and filtered, and the solvent
evaporated in vacuo. The residue was purified by MPLC (20% EtOAc
in hexane) to give 100 mg (66%) of a colorless oil.
To a stirred solution of 100 mg (0.34 mmol) of the phosphine oil in
10 mL ethyl acetate was added 100 mg (0.54 mmol) of m-CPBA, and
the solution was stirred 30 min. The solution was washed with saturated
aqueous Na2CO3 and brine, dried over Na2SO4, and filtered, and the
solvent evaporated in vacuo. The residue was purified by MPLC (70%
EtOAc in hexane) to yield 100 mg (95%) of 41 as a white solid. Mp
) 152-153 °C (lit.30 158-159 °C). 31P NMR (121 MHz) δ 35.5. 1H
NMR (400 MHz) δ 4.58 (s, 2H), 5.50 (br s, 1H), 6.99-7.06 (m, 1H),
7.26 (t, J ) 8.0 Hz, 1H), 7.46-7.64 (m, 12H). 13C NMR (100 MHz)
δ 64.64 (d, J ) 5.0 Hz), 127.16 (d, J ) 13.8 Hz), 128.65 (d, J ) 12.5
Hz), 130.78, 131.22, 131.54 (d, J ) 11.3 Hz), 132.00 (d, J ) 10.0
Hz), 132.27, 132.75, 133.65 (d, J ) 12.5 Hz), 146.58 (d, J ) 7.5 Hz).
Anal. Calcd for C19H17O2P: C, 74.02; H, 5.56. Found: C, 73.99; H,
5.56.
Endocyclic Restriction Test of 20 and 20-d12. An approximate
1:1 mixture of 127 mg (0.29 mmol) of 20 and 20-d12 was dissolved in
29 mL of THF and an aliquot was removed for FABMS analysis. To
the solution cooled to -78 °C was added 610 µL (0.61 mmol) of 1.0
M tert-butyllithium, and the solution was stirred 30 min at -78 °C.
The reaction mixture was quenched with water and stirred 5 min, and
ethyl acetate was added. The organic layer was separated, washed with
brine, dried over sodium sulfate and filtered, and the solvent evaporated
in vacuo. The residue was purified by MPLC (70% EtOAc in hexane)
to yield 43 mg (47%) of 41 as a white solid. Mp ) 152-153 °C. 31
NMR (121 MHz) δ 35.44. For isotopic analysis see Table 2.
P
Conversion of Phosphinite 18 to Phosphine 35. To a solution of
231 mg (0.54 mmol) of 18 in 4.05 mL of THF cooled to -78 °C was
added 735 µL (0.72 mmol) of 1.02 M tert-butyllithium, and the solution
was stirred 1 min at -78 °C. The reaction mixture was quenched with
saturated aqueous NaHSO3 and ethyl acetate was added. The organic
layer was separated and washed with brine, dried over sodium sulfate,
and filtered and the solvent evaporated in vacuo. The residue was
purified by MPLC (30% EtOAc in hexane) to yield 39 mg (24%) 35
as a colorless oil. 31P NMR (162 MHz) δ -14.80. 1H NMR (400
MHz) δ 1.63 (br s, 1H), 3.14 (t, J ) 6.8 Hz, 2H), 3.80 (t, J ) 6.8 Hz,
2H), 6.88-6.91 (m, 1H), 7.12-7.16 (m, 1H), 7.23-7.34 (m, 12H).
13C NMR (100 MHz) δ 37.69 (d, J ) 19.9 Hz), 63.39 (d, J ) 3.1 Hz),
126.82, 128.54 (d, J ) 6.9 Hz), 128.74, 129.08, 129.94 (d, J ) 5.3
Hz), 133.79 (d, J ) 19.8 Hz), 133.92, 135.95 (d, J ) 8.2 Hz), 136.48
(d, J ) 9.1 Hz), 142.97 (d, J ) 25.9 Hz). FIMS m/z 306.
Conversion of Phosphinite Borane 21 to Phosphine Borane 43.
To a solution of 500 mg (1.16 mmol), 21 in 7.7 mL, THF cooled to
-78 °C was added 1.8 mL (2.34 mmol) of 1.3 M tert-butyllithium,
and the solution was stirred 5 min at -78 °C. The reaction mixture
was quenched with water, and the THF was evaporated in vacuo. The
solution was extracted with diethyl ether, dried with sodium sulfate,
and filtered, and the solvent evaporated in vacuo. The residue was
purified by flash chromatography (10-30% EtOAc in hexane) to yield
155 mg (44%) 43 as a white solid. Mp ) 152-154 °C. 31P NMR
(162 MHz) δ 21.2 (q, J ) 59 Hz). 1H NMR (400 MHz) δ 0.6-1.7 (br
m, 3H), 2.49 (br s, 1H), 4.49 (d, J ) 6.1 Hz, 2H), 6.82-6.88 (m, 1H),
7.14-7.18 (m, 1H), 7.35-7.40 (m, 4H), 7.43-7.48 (m, 7H), 7.50-
7.57 (m, 1H). 13C NMR (100 MHz) δ 63.06 (d, J ) 6.1 Hz), 127.37
(d, J ) 12.2 Hz), 127.69 (d, J ) 8.4 Hz), 128.76 (d, J ) 58.7 Hz),
128.95 (d, J ) 10.7 Hz), 130.97 (d, J ) 9.1 Hz), 131.48 (d, J ) 3.0
Hz), 131.93 (d, J ) 3.0 Hz), 133.11 (d, J ) 10.0 Hz), 134.01 (d, J )
6.1 Hz), 145.15 (d, J ) 11.5 Hz).
Oxidation of phosphine 35 with m-CPBA affords phosphine oxide
1
38 with 31P and H NMR identical to above.
An additional experiment where the product mixture was oxidized
with m-CPBA indicated three phosphorus containing products: (o-(2-
hydroxyethyl)phenyl)diphenylphosphine oxide (38, 43%), phenethyl
diphenylphosphinate (39, 41%), and t-butyldiphenylphosphine oxide
(40, 16%). 39: 31P NMR (162 MHz) δ 32.13. 1H NMR (400 MHz)
δ 3.04 (t, J ) 6.8 Hz, 2H), 4.18-4.24 (m, 2H), 7.19-7.32 (m, 5H),
7.37-7.51 (m, 6H), 7.67-7.72 (m, 4H). 40: 31P NMR (162 MHz) δ
39.57. 1H NMR (400 MHz) δ 1.23 (d, J ) 14.9 Hz, 9H), 7.43-7.52
(m, 7H), 7.92-7.96 (m, 3H).
Phosphinite borane 43 was converted to phosphine oxide 41.
A
solution of 30 mg (0.10 mmol) of 36 in 1 mL of diethylamine was
heated for 2 h at reflux. The diethylamine was evaporated in vacuo,
and 5 mL of ether was added. To the solution was added 30 of mg
m-CPBA, and the solution was stirred 1 h. The reaction mixture was
wasted with 10% aqueous NaOH solution, dried over sodium sulfate,
and filtered, and the solvent removed in vacuo to yield 30 mg (98%)
of 41 as a white solid. 31P NMR (121 MHz) δ 35.5. 1H NMR (400
MHz) δ 4.58 (s, 2H), 5.79 (br s, 1H), 7.00-7.06 (m, 1H), 7.24-7.29
(m, 1H), 7.47-7.64 (m, 12H).
Endocyclic Restriction Test of 18 and 18-d12. A solution of 151
mg (0.350 mmol) of 2-(o-iodophenethyl) diphenylphosphinite (18) and

The Endocyclic Restriction Test
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9061
Endocyclic Restriction Test of 21 and 21-d12. A mixture of 98.7
mg (0.23 mmol) of 21 and 86.4 mg (0.20 mmol) 21-d7 was prepared,
and an aliquot was submitted for isotopic analysis (see Table 3). To
a solution of 68.0 mg (0.16 mmol) of the above mixture dissolved in
2.0 mL of THF and cooled to -78 °C was added 240 µL (0.31 mmol)
of 1.3 M tert-butyllithium, and the solution was stirred 5 min. The
reaction mixture was quenched with water, and THF was removed in
vacuo. The residue was dissolved in ether, washed with saturated
aqueous NaCl solution, dried over sodium sulfate, and filtered, and
solvent was removed in vacuo. The residue was purified by flash
chromatography on silica (30% EtOAc in hexane) to yield 21.0 mg
NMR (400 MHz) δ 1.95 (s, 3H), 3.26 (dt, J ) 13.9, 7.1 Hz, 1H), 3.31
(dt, J ) 13.9, 7.1 Hz, 1H), 4.18 (t, J ) 7.1 Hz, 2H), 7.08-7.12 (m,
1H), 7.18-7.19 (m, 1H), 7.40-7.70 (m, 10H), 7.87-7.93 (m, 3H),
8.26 (d, J ) 13.9 Hz, 1H). 13C NMR (100 MHz) δ 20.95, 33.39 (d, J
) 4.6 Hz), 64.41, 126.08 (d, J ) 7.0 Hz), 126.81 (d, J ) 10.7 Hz),
127.00, 127.86, 128.31, 128.50 (d, J ) 16.8 Hz), 128.85 (d, J ) 29.0
Hz), 129.27, 130.44 (d, J ) 34.3 Hz), 131.64, 131.75, 131.94, 132.01,
132.04, 132.17, 132.32 (d, J ) 15.2 Hz), 132.90 (d, J ) 75.5 Hz),
133.89 (d, J ) 12.9 Hz), 134.68 (d, J ) 2.3 Hz), 143.23 (d, J ) 8.4
Hz), 170.93. FABMS m/z 107(22), 120(14), 136(74), 137(62), 138-
(33), 139(16), 154(100), 155(28), 289(13), 307(24), 355(19), 415(69),
416(22). HRMS (FAB) m/z (M + H)+ calcd 415.1463, obsd 415.1463.
Determination of the Enantiomeric Ratio of (S)-38. Analyses
were performed on a Rainin analytical HPLC system using a tandem
silica column and Pirkle â-GEM column with 25% isopropyl alcohol
in hexane at 1.25 mL/min.
Determination of the Enantiomeric Ratio of (R)-28. A solution
of 15 mg (0.06 mmol) of (R)-28 and 19 mg (0.06 mmol) of (S)-(+)-
N-(3,5-dinitrobenzoyl)-R-methylbenzylamine in 500 µL of CDCl3 was
prepared and placed in a 5 mm NMR tube. The 31P NMR spectrum
was obtained at 162 MHz, and two peaks were observed.
Conversion of Phosphinate (S)-27 to Phosphine Oxide (S)-33. A
solution of 0.10 M (S)-27 in THF was prepared by dissolving 147 mg
(0.30 mmol) of (S)-27 in 3 mL of THF. A 1.5 mL (0.15 mmol) aliquot
was removed and cooled to -78 °C. To this solution was added 310
µL (0.29 mmol) of 0.95 M t-butyllithium, and the solution was stirred
1 min. The reaction mixture was quenched with water, ether extracted,
dried over magnesium sulfate, and filtered, and solvent evaporated in
vacuo. The residue was purified by MPLC (50% to 100% EtOAc in
hexane) to yield 7.5 mg (14%) (S)-33. 31P NMR (162 MHz) δ 35.8.
1H NMR (400 MHz) δ 3.08-3.11 (m, 2H), 3.90-3.93 (m, 2H), 6.97-
6.99 (m, 1H), 7.02-7.05 (m, 1H), 7.42-7.68 (m, 10H), 7.86-7.93
(m, 3H), 8.20 (d, J ) 14.0 Hz, 1H).
Typical Conditions for the Conversion of (R)-25 to (S)-33. A
solution of 0.09 M (R)-25 in THF was prepared by dissolving 657 mg
(1.32 mmol) of (R)-25 in 14 mL of THF. A 7 mL (0.66 mmol) aliquot
was removed and cooled to -78 °C. To the solution was added 1.02
mL (1.32 mmol) of t-butyllithium, and the solution was stirred 1 min.
The reaction mixture was quenched with water, and the THF evaporated
in vacuo. The mixture was extracted with ether, dried over magnesium
sulfate, and filtered, and solvent removed in vacuo. To the residue
(R-)-39 was added 10 mL of diethylamine, and the solution was heated
to reflux for 2 h. The amine was removed in vacuo, and to the residue
was added 10 mL of ether and 100 mg of 55% m-CPBA. The solution
was stirred 0.5 h. The reaction mixture was washed with 5% aqueous
NaOH solution and brine, dried over magnesium sulfate, and filtered
and the solvent evaporated in vacuo. The residue was purified by
MPLC (50% to 100% EtOAc in hexane) to yield 14.2 mg of (3%)
(S)-33. 31P NMR (162) δ 35.9.
1
(44%) of phosphine borane 43. 31P NMR (162 MHz) δ 18.7 (m). H
NMR (400 MHz) δ 4.59 (s, 1H), 6.90-6.95 (m, 1H), 7.23-7.27 (m,
2H), 7.45-7.59 (m, 5H), 7.63-7.66 (m, 1H). A solution of 21.0 mg
(0.07 mmol) of 43 in 1.0 mL of diethylamine was heated at reflux for
2 h. The diethylamine was evaporated in vacuo, and the residue was
dissolved in 1 mL of diethyl ether. To the ethereal solution was added
25 mg of m-CPBA and stirred 30 min. The reaction mixture was
washed with saturated aqueous Na2CO3 and brine, dried over sodium
sulfate, and filtered, and the solvent was removed in vacuo to yield
14.6 mg (70%) of 51. 31P NMR (162 MHz) δ 35.54, 35.57. For
isotopic analysis see Table 3.
Conversion of Phosphinite (R)-26 to Phosphine (S)-33. A solution
of 0.11 M (R)-26 in THF was prepared by adding 16 mL of THF to
824 mg (1.71 mmol) of (R)-26. A 4 mL aliquot (0.21 mmol) was
removed and cooled to -78 °C. To this solution was added 330 µL
(0.43 mmol) of 1.3 M tert-butyllithium. After 1 min the reaction was
quenched and oxidized with 50 µL of 30% aqueous hydrogen peroxide
solution. The THF was evaporated in vacuo, and ether was added.
The solution was washed with saturated sodium bisulfite solution and
brine, dried over magnesium sulfate, and filtered, and solvent removed
in vacuo. The residue was purified by MPLC (50% to 100% EtOAc
in hexane) to yield 33.0 mg (41%) phosphine oxide (S)-33 as a colorless
oil. 31P NMR (162) δ 35.98. 1H NMR (400 MHz) δ 3.07 (dt, J )
5.1, 8.8 Hz, 1H), 3.11 (dt, J ) 5.1, 8.8 Hz, 1H), 3.92 (t, J ) 5.5 Hz,
2H), 6.96-7.02 (m, 1H), 7.15-7.19 (m, 1H), 7.43-7.67 (m, 10H),
7.86-7.93 (m, 3H), 8.19 (d, J ) 14.2 Hz, 1H). 13C NMR (100 MHz)
δ 37.21 (d, J ) 4.6 Hz), 63.91, 125.76 (d, J ) 3.7 Hz), 126.75 (d, J
) 11.7 Hz), 127.05, 127.86, 128.50 (d, J ) 21.4 Hz), 128.58 (d, J )
18.3 Hz), 128.80 (d, J ) 25.9 Hz), 129.72, 130.56, 131.58 (d, J )
14.5 Hz), 131.63 (d, J ) 9.2 Hz), 132.02 (d, J ) 9.9 Hz), 132.17 (d,
J ) 2.3 Hz), 132.38 (d, J ) 13.0 Hz), 132.75 (d, J ) 2.3 Hz), 133.26,
133.39, 133.83 (d, J ) 1.6 Hz), 134.73 (d, J ) 2.3 Hz). FABMS m/z
107(19), 120(11), 136(66), 137(56), 138(32), 139(15), 154(100), 155-
(26), 289(15), 307(26), 355(10), 373(97), 374(28). HRMS (FAB) m/z
(M + H)+ calcd 373.1357, obsd 373.1352.
Arbuzov Conditions for Conversion of (R)-26 to (R)-28. To a
solution of 397 mg (0.82 mmol) of (R)-26 in 1 mL THF was added 51
µL (0.82 mmol) of methyl iodide, and the solution was stirred for 16
h. The THF was evaporated in vacuo and purified by MPLC (EtOAc)
to yield 177 mg (82%) of methylnaphthylphenylphosphine oxide (R)-
28. Mp ) 145-146 °C (lit.31 Mp 146-147 °C). 31P NMR (162 MHz)
δ 30.66 1H NMR (400 MHz) δ 2.11 (d, J ) 13.2 Hz, 3H), 7.45-7.66
(m, 6H), 7.74-7.79 (m, 2H) 7.86-7.94 (m, 3H), 8.36 (d, J ) 13.4
Hz, 1H). EIMS (70 eV) m/z 267 (11), 266 (66), 265 (100), 251 (39),
Acknowledgment. We are grateful to the National Science
Foundation and the National Institutes of Health for the support
of this work. M.T. is also grateful to the Eastman Chemical
Company, the Department of Education and the University of
Illinois for fellowship support. This article is dedicated to
Nelson J. Leonard, a valued colleague and friend, for the
occasion of his 80th birthday.
127 (15), 77 (11). [R]D ) +13 ( 2° (c 1.34, MeOH). (lit. [R]D
+12°).
)
Conditions for the Acylation of (S)-33. To a solution of 77 mg of
(S)-33 in 5 mL of dichloromethane was added 25 mg of DMAP, 33
µL of pyridine, and 30 µL of acetyl chloride. The solution was stirred
16 h. The reaction mixture was washed with 5% aqueous HCl solution,
5% aqueous NaOH solution, and brine, dried over magnesium sulfate,
and filtered, and solvent evaporated in vacuo to afford (S)-46. No
further purification was performed. 31P NMR (162 MHz) δ 32.38. 1H
Supporting Information Available: The preparation of
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JA961375G