Synthesis of new 1,3-oxaphosphorinanium salts. Stereochemistry of hydroxide-induced displacement of methoxide ion

Article abstract of DOI:10.1021/jo050901w

The synthesis of pure cis- and trans-3-methoxy-2,2,6-trimethyl-3-phenyl-1, 3-oxaphosphorinanium tetrafluoroborate salts 3a and 3b, respectively, molecules designed to evaluate the effect of oxygen on the steric course of base-induced nucleophilic displace

Full text of DOI:10.1021/jo050901w

Synthesis of New 1,3-Oxaphosphorinanium Salts. Stereochemistry
of Hydroxide-Induced Displacement of Methoxide Ion
Susana Lo´pez-Cortina,† Danute I. Basiulis,‡ Kenneth L. Marsi,‡
Miguel Angel Mun˜oz-Herna´ndez,† Mario Ordon˜ez,† and Mario Ferna´ndez-Zertuche*,†
Centro de Investigaciones Quı´micas, Universidad Auto´noma del Estado de Morelos, Avenida Universidad
1001, Col. Chamilpa, 62210, Cuernavaca, Morelos, Me´xico, and Department of Chemistry and
Biochemistry, California State University, 1250 Bellflower Boulevard, Long Beach, California 90840
mfz@ciq.uaem.mx
Received May 5, 2005
The synthesis of pure cis- and trans-3-methoxy-2,2,6-trimethyl-3-phenyl-1,3-oxaphosphorinanium
tetrafluoroborate salts 3a and 3b, respectively, molecules designed to evaluate the effect of oxygen
on the steric course of base-induced nucleophilic displacement of the methoxy group at phosphorus,
was accomplished. It was found that these isomeric salts react with aqueous sodium hydroxide to
produce the corresponding phosphine oxides 7a and 7b with complete retention of configuration at
phosphorus.
Introduction
the other hand, depending on the specific compound,
phospholanium salts have been observed to cleave with
complete retention of configuration4 or to produce mix-
tures of stereoisomers.5 Both mechanistic and stereo-
chemical arguments have been proposed to explain these
differences.
In six-membered rings, the most studied leaving group
has been the benzyl group attached to the phosphorus
atom, and the base cleavage reaction with aqueous
sodium hydroxide ion has been found to be nonstereospe-
cific. When pure samples of cis and trans isomers (phenyl
and methyl cis or trans) of 1-benzyl-4-methyl-1-phenyl
phosphorinanium bromides 1a and 1c (Scheme 1) were
reacted with aqueous NaOH under identical conditions,
mixtures of different proportions of oxides 2a and 2b
were obtained.6 When a more electronegative group than
benzyl was used (i.e., methoxy group), 1b and 1d reacted
with base to produce the same phosphine oxides 2a or
2b with complete inversion of configuration at phospho-
rus.5
It has long been known that quaternary phosphonium
salts undergo nucleophilic displacement reactions by
aqueous hydroxide ion to produce phosphine oxides1 and
that the cleavage of acyclic phosphonium salts occurs
with inversion of configuration at phosphorus.2 In this
regard, there has been considerable interest in the
stereochemical behavior of phosphorus in cyclic systems
in which phosphorus is the only heteroatom in the ring.
In cyclic systems, however, ring size has been implicated
as having a pronounced effect on the steric course of the
nucleophilic displacement of exocyclic substituents at
phosphorus. Phosphetanium salts have been shown to
be converted to the corresponding phosphine oxides with
complete retention of configuration at phosphorus.3 On
† Universidad Auto´noma del Estado de Morelos.
‡ California State University.
(1) (a) Frey, P. A. Tetrahedron 1982, 38, 1541. (b) Bruzik, K.; Tzay,
M. D. J. Am. Chem. Soc. 1984, 106, 747. (c) McEwen, W. E.; Kumli, K.
F.; Blade-Font, A.; Zanger, M.; Vander Werf, C. A. J. Am. Chem. Soc.
1964, 86, 2378. (d) Zanger, M.; VanderWerf, C. A.; McEwen, W. E. J.
Am. Chem. Soc. 1959, 81, 3806. (e) Horner, L.; Winkler, H.; Rapp, A.;
Mentrup, A.; Hoffmann, H.; Beck, P. Tetrahedron Lett. 1961, 161.
(2) (a) Zon, G.; De Bruin, K. E.; Naumann, K.; Mislow, K. J. Am.
Chem. Soc. 1969, 91, 7023. (b) Blade-Font, A.; Vander Werf, C. A.;
McEwen, W. E. J. Am. Chem. Soc. 1960, 82, 2396. (c) Luckenback, R.
Z. Naturforsch. 1976, 31b, 1127. (d) Luckenback, R. Phosphorus 1972,
1, 223. (e) Luckenback, R. Phosphorus 1972, 1, 229.
(3) (a) Hawes, W.; Trippett, S. J. Chem. Soc. C 1969, 1465. (b)
Cremer, S. E.; Chorvat, R. J.; Trivedi, B. C. Chem. Commun. 1969,
769.
(4) (a) Marsi, K. L. J. Am. Chem. Soc. 1969, 91, 4724. (b) Marsi, K.
L.; Burns, F. B.; Clark, R. T. J. Org. Chem. 1972, 37, 238. (c) Marsi,
K. L.; Co-Sarno, M. E. J. Org. Chem. 1977, 42, 778.
(5) Marsi, K. L. J. Org. Chem. 1975, 40, 1779.
(6) Marsi, K. L.; Clark, R. T. J. Am. Chem. Soc. 1970, 92, 3792.
10.1021/jo050901w CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/19/2005
J. Org. Chem. 2005, 70, 7473-7478
7473

Lo´pez-Cortina et al.
SCHEME 2a
FIGURE 1. 1,3-Oxaphosphorinanium salts for stereochemical
study.
a Key: (i) n-BuLi, THF, 0 °C; (ii) 2-methyloxetane, 5, -78 °C;
(iii) p-TsOH, acetone, C6H6; (iv) t-BuOOH, C6H6.
SCHEME 1
SCHEME 3a
a Key: (i) column chromathography: silica gel (230-400),
acetone.
On the basis of the later study, we herein report our
results on the hydroxide-induced displacement of the
methoxide group from pure samples of cis and trans
isomers of 3-methoxy-2,2,6-trimethyl-3-phenyl-1,3-ox-
aphosphorinanium tetrafluoroborate salts 3a and 3b
(Figure 1), systems designed to study the effect of a
second heteroatom in the cyclic system on the stereo-
chemistry of this type of reactions. The literature contains
a number of examples of six-membered rings containing
both oxygen and phosphorus. These compounds, however,
are of either the 1,2-oxaphosphorinane7 or 1,3,2-diox-
aphosphorinane type, where several stereochemical stud-
ies have been carried out on the latter.8 The 1,3-
oxaphosphorinane system is much more difficult to
synthesize and therefore has not been studied as exten-
sively.
In contrast to five-membered rings where the presence
of the oxygen atom has no effect in the stereochemical
course of the reaction,4c in our study the presence of
oxygen on the ring does induce a different stereochemical
outcome, and to our surprise, the reaction of 3a and 3b
with base proceeds with complete retention of configu-
ration at phosphorus to yield phosphine oxides 7a and
7b, instead of inversion (as in 1b and 1d).
salt of phenylphosphine 4, previously synthesized by
reduction of dicholorophenylphosphine.10 In fact, this
procedure allowed us to obtain compound 6 as the major
product of the reaction (54% yield). In the following steps,
the cyclization toward oxides 7 was carried out following
Marsi’s adaptation of Oehme’s procedure4c,11 for the
synthesis of 1,3-oxaphospholanes with the proper adjust-
ment of the temperature and reaction time. Thus, when
compound 6 was heated at temperatures below 100 °C
with acetone and in the presence of p-toluenesulfonic acid
during an 84 h period, followed immediately by treatment
with tert-butylhydroperoxide in benzene, the desired
cyclic phosphine oxides 7 were obtained as a mixture of
the cis and trans diastereoisomers (13% yield from 6).
The separation of the diastereomeric mixture of oxides
7 was accomplished by column chromatography leading
to diastereoisomers 7a and 7b in a very pure form
(Scheme 3).
Both compounds were fully characterized by NMR
spectroscopy; however, to carry out the stereochemical
study, it was necessary to establish the relative stereo-
chemistry of these compounds. The assignment of the
relative configurations of diastereoisomers 7a and 7b was
unambiguously established by an X-ray crystal structure
determination of 7a.12 Unfortunately, an appropriate
crystal of 7b could not be obtained for X-ray studies.
Figure 2 shows the X-ray crystal structure of 7a in which
it can be observed that the six-membered ring adopts a
flattened chair conformation where the methyl group at
C(6) occupies an equatorial position and the phenyl
substituent at phosphorus an axial position, establishing
Results and Discussions
Of prime importance for the synthesis of 3a and 3b
was the development of a synthetic route to the key
intermediate 3-hydroxybutylphenylphosphine 6 (Scheme
2). It was anticipated that 6 could be prepared by the
selective ring-opening reaction of 2-methyloxetane 5
(prepared following Searles’ procedure9), by the lithium
(7) Hanaya, T.; Akamatsu, A.; Kawase, S.; Yamamoto, H. J. Chem.
Res., Synop. 1995, 194.
(8) (a) Rowell, R.; Gorenstein, D. G. J. Am. Chem. Soc. 1981, 103,
5894. (b) Chang, J. A.; Gorenstein, D. G. Tetrahedron 1987, 43, 5187.
(c) Gordillo, B.; Eliel, E. L. J. Am. Chem. Soc. 1991, 113, 2172.
(9) Searles, S., Jr.; Pollart, K. A.; Block, F. J. Am. Chem. Soc. 1957,
79, 952.
(10) Kuchen, W.; Buchwald, H. Chem. Ber. 1958, 91, 2296.
(11) (a) Oehme, H.; Issleib, K.; Leissring, E. Tetrahedron, 1972, 28,
2587. (b) Issleib, K.; Oehme, H.; Scheibe, M. Synth. Inorg. Metal-Org.
Chem. 1972, 2, 223. (c) Zschunke, A.; Meyer, H.; Leissring, E.; Oehme,
H.; Issleib, K. Phosphorus Sulfur 1978, 5, 81.
(12) Crystal structure of compound 7a has been deposited at the
Cambridge Crystallographic Data Centre (CCDC 270336).
7474 J. Org. Chem., Vol. 70, No. 19, 2005

Synthesis of New 1,3-Oxaphosphorinanium Salts
TABLE 1. 1H NMR Data of Isomers 7a and 7b
δ, ppm (multiplicity,
J (Hz)) for 7a
δ, ppm (multiplicity,
J (Hz)) for 7b
proton
CH3(e)
1.26 (d,13.6)
1.70 (d,11.6)
1.29 (d, 6.0)
2.12 (m)
4.1 (ddq, 2.0, 11.1, 6.0)
7.51 (m)
1.38 (d, 12.0)
CH3(a)
1.27 (d, 13.6)
1.28 (d, 6.0)
2.22 (m)
CH3(6)
CH2-CH2
CH
C6H5(meta)
C6H5(para)
C6H5(ortho)
4.0 (ddq, 2.0, 11.0, 6.0)
7.48 (m)
7.55 (m)
7.78 (m)
7.57 (m)
8.11 (m)
confirmed by the torsion angles O(15)-C(14) (2.81°) and
O(15)-C(10) (178.4°). The other four torsional angles
involving the P(3)-C(9) fragment provide additional
evidence for the observed orientation of the phenyl group.
In support of this behavior, a parallel conformation of
an axial phenyl group has been assumed for 5-phenyl-
1,3-dioxanes.16 Presumably, the methyl groups at C(2)
and/or the absence of an axial hydrogen in the adjacent
position (at the ring oxygen) cause the different confor-
mational behavior of 7a; however, this cannot be deter-
mined only on the basis of the data reported here.
Some independent facts support the stereochemical
assignments given to the isomeric oxides 7a and 7b. The
1H NMR spectra of these compounds support a configu-
rational assignment (Table 1) in which the methyl group
at C-6 occupies an equatorial position in both isomers
since axial-axial three-bond coupling constants for the
H5-H6 protons are observed with values of 11.1 Hz for
7a and of 11.0 Hz for 7b. In 7a, there is a difference of
0.44 ppm in the proton shifts of the methyl groups at
C(2), presumably due to the shielding exerted by the
phenyl group on the equatorial methyl, rather than on
the axial one. Thus, in the spectrum of 7b, the difference
in the chemical shifts of the methyl groups at C(2) (0.11
ppm) is less pronounced than in 7a, due to the marked
shielding effect of the phenyl substituent on the axial
methyl. Therefore, when comparing the chemical shifts
of the axial methyl group at C(2) on both isomers, a
greater shielding effect of the phenyl group can be
assumed when it occupies an equatorial position (7b)
than when it is in an axial position (7a). The relationship
between the C(2) methyl groups and the PdO group
provides additional support to our stereochemical assign-
ment. The coupling constant (3J) between these methyl
groups and the phosphorus atom on the PdO function
should have a lower magnitude when they have a cis
disposition than when they have a trans disposition. In
addition, the chemical shift of the methyl groups cis to
the PdO functionality should be more downfield than the
chemical shift of the methyl groups trans to the PdO
group.17 Moreover, the order of elution, 7a > 7b, is in
accord with the predicted higher dipole moment of 7b,
which leads to stronger retention on the column. In
FIGURE 2. X-ray structure of phosphine oxide 7a, cis
configuration (CH3-Ph).
a cis relationship between them. It is then assumed that
in diastereoisomer 7b, the methyl and the phenyl groups
must have a trans relationship. The fact that the ring
system is appreciably flattened at the phosphorus end
is suggested by the torsional angles involving the central
fragment P(3)-C(2), Table 6s (Supporting Information).
These angles are all far from the ideal angle of 60° for
gauche conformations and the 180° angle for anti con-
formations by approximately 20°. In addition, the widen-
ing of the C(5)-C(4)-P(3) (115.2°), C(4)-P(3)-0(15)
(113.2°), and C(2)-P(3)-O(15) (114°) bond angles and a
diminished C(2)-P(3)-C(4) (103.5°) internal ring angle
can be observed, Table 3s (Supporting Information). The
net effect is to alleviate the crowding generated when the
phosphorus substituent occupies an axial position, as has
been reported for similar compounds.13 In contrast, the
O(1)-C(6)-C(5)-C(4) torsion angle at nearly 60° and the
C(16)-C(6)-C(5)-C(4) torsion angle at nearly 180° show
a normal chair conformation shape at C(6). Incidentally,
this latter angle (178.43°) also proves that the methyl
group at C(6) occupies an equatorial position in 7a, and
by analysis of its very similar proton (Table 1) and 13C
NMR signals, this methyl group also occupies an equato-
rial position in 7b.
It has been known that an axial phenyl group assumes
a conformation in which it is perpendicular to the
symmetry plane of the chair-shaped cyclohexane ring,
avoiding 1,3-syn diaxial repulsions between the aromatic
ortho hydrogens and the cyclohexane ring hydrogens.14
This also applies for some 1-phenyl-phosphorinane de-
rivatives, based on X-ray studies.15 In contrast, it is
observed in the crystal structure of 7a that the axial
phenyl substituent bisects the phosphorinane ring as
(13) Featherman, S. I.; Quin, L. D. J. Am. Chem. Soc. 1975, 97, 4349.
(14) (a) Hodgson, D. J.; Rychlewska, U.; Eliel, E. L.; Manoharan,
M.; Knox, D. E.; Olefirowicz, E. M. J. Org. Chem. 1985, 50, 4838. (b)
Wiberg, K. B.; Castejon, H.; Bailey, W. F.; Ochterski, J. J. Org. Chem.
2000, 65, 1181. (c) Stereochemistry of Organic Compounds; Eliel, E.
L., Wilen, S. H., Eds.; John Wiley and Sons: New York, 1994.
(15) (a) Allinger, N. L.; von Voithenberg, H. Tetrahedron 1978, 34,
627. (b) McPhail, A. T.; Breen, J. J.; Quin, L. D. J. Am. Chem. Soc.
1971, 93, 2574. (c) Rampal, J. B.; Berlin, K. D.; Edasery, J. P.;
Satyamurthy, N. J. Org. Chem. 1981, 46, 1166.
(16) Huang, Y.; Bentrude, W. G. J. Am. Chem. Soc. 1995, 117, 12390.
J. Org. Chem, Vol. 70, No. 19, 2005 7475

Lo´pez-Cortina et al.
SCHEME 4
SCHEME 5
diasteroisomer 7a, the dipoles are oriented in opposite
directions, whereas in 7b, the dipoles are oriented in the
same direction.
1
direct comparison of the H and 31P NMR spectra of the
isolated phosphine oxides of the substitution products
with those of the phosphine oxides previously used as
precursors for the synthesis of 3a and 3b since they are
exactly the same compounds. The stereochemical behav-
ior observed in our study dramatically contrasts the
stereochemical behavior reported by Marsi in six-
membered rings with phosphorus as the only heteroatom
where the base-induced displacement of a methoxy group
proceeds with complete inversion of configuration at
phosphorus.
Once the configurations of the phosphine oxides 7a and
7b were established, the required molecules for our study,
3a and 3b, were obtained by direct methylation of 7a and
7b with trimethyloxonium tetrafluoroborate. The config-
uration of 3a and 3b was assigned on the basis of the
established configuration of their parents, 7a and 7b,
respectively, and the known fact that methylation of
phosphine oxides with trimethyloxonium tetrafluorobo-
rate proceeds with retention of configuration at phos-
phorus (Scheme 4).18 Some key NMR signals were used
for the structural determination of these compounds; for
example, the signals for the methoxy groups on both
isomers appear as doublets centered around 4.0 ppm as
a result of the coupling of these protons with the adjacent
To explain the observed stereochemistry in these
reactions, the reduced ring strain in six-membered rings
with phosphorus as the only heteroatom as compared
with phosphetanes and phospholanes must be taken into
account since this allows the bonds directly attached to
phosphorus in the six-membered ring to occupy equato-
rial-equatorial or equatorial-apical positions in the
trigonal bipyramid phosphorane intermediates involved
in these type of reactions. The pathway toward inversion
reported for 1b and 1d was explained by an SN2(P)
mechanism involving a phosphorane in which the six-
membered ring can be placed in an equatorial-equatorial
position as an intermediate. However, in 3a and 3b, this
arrangement presumably could be less favorable, and a
phosphorane with the six-membered ring in equatorial-
apical positions can be suggested in order to alleviate the
ring strain caused by the presence of the oxygen in the
ring and a geminal methyl group at C(2).
On the basis of the latter and on the different mech-
anisms that have been proposed in the literature for the
nucleophilic substitution at phosphorus in cyclic com-
pounds, the mechanism involving Berry pseudorota-
tions19 of phosphoranes is the one that best explains our
results. The pathway toward retention of configuration,
taking 3a as an example (Scheme 6), involves an apical
attack of the OH species to produce phosphorane 8. A
pseudorotation toward phosphorane 9 places the OCH3
leaving group in an apical position, and the base-induced
elimination of this group in phosphorane 9 leads to oxide
7a with retention of configuration. This condition of
apical attack and apical departure is well supported by
the extended principle of microscopic reversibility, which
establishes that apical bonds are longer and weaker.20
In addition, according to the scale of relative apicophi-
3
phosphorus atom. Likewise, the JP-H(OCH ) coupling
3
constants have similar values of 11.0 and 11.4 Hz and
are in agreement with the values previously reported by
Marsi5 for phosphorus cyclic compounds. The signals of
the methyl groups at C(2) of isomers 3a and 3b show
similar chemical shifts according of these groups in the
corresponding oxides. The chemical shifts of methyl
groups cis to the methoxy group (CH3 axial in 3a and
CH3 equatorial in 3b) are downfield in relation to the
signals of these methyl groups on the oxides 7a and 7b.
This is due to the change of the substituent at phosphorus
from oxygen to methoxy. In addition, the difference
between the chemical shifts of the geminal methyl groups
is less pronounced in the trans isomer 3b than in the cis
isomer 3a, as it is observed for 7b and 7a, respectively.
Finally, the 31P NMR signals for each isomer appear at
+67.27 ppm for 3a and +69.97 ppm for 3b.
The nucleophilic displacement reactions in aqueous
sodium hydroxide carried out on salts 3a and 3b led, to
our surprise, to the formation of phosphine oxides 7a and
7b, respectively, with complete retention of configuration
at phosphorus (Scheme 5) for both. The stereochemistry
observed in our study could be easily corroborated by
(17) (a) Rudi, A.; Kashman, Y. Tetrahedron Lett. 1978, 2209. (b)
Bodalski, R.; Pietrusiewicz, K. M.; Koszuk, J. Tetrahedron 1975, 31,
1907. (c) Gray, G. A.; Cremer, S. E.; Marsi, K. L. J. Am. Chem. Soc.
1976, 98, 2109.
(18) (a) Meerwein, H. Org. Synth. 1966, 6, 120. (b) Heine, H. W.;
Newton, T. A.; Blosick, G. J.; Irving, K. C.; Meyer, C.; Corcoran, G. B.,
III. J. Org. Chem. 1973, 38, 651. (c) von Hellman, H.; Bader, J.;
Birkner, H.; und Schumacher, O. Liebigs Ann. Chem. 1962, 48, 659.
(d) House, H. O.; Richey, F. A., Jr. J. Org. Chem. 1969, 34, 1430. (e)
Marsi, K. L.; Jasperse, J. L. J. Org. Chem. 1978, 43, 760. (f) Zon, G.;
DeBruin, K. E.; Naumann, K.; Mislow, K. J. Am. Chem. Soc. 1969,
91, 7023.
(19) Berry, R. S. J. Chem. Phys. 1960, 32, 933.
(20) Gillespie, P.; Ramirez, F. H.; Ugi, I.; Marquarding, D. Angew.
Chem., Int. Ed. Engl. 1973, 12, 91.
7476 J. Org. Chem., Vol. 70, No. 19, 2005

Synthesis of New 1,3-Oxaphosphorinanium Salts
SCHEME 6
SCHEME 7
Conclusion
We have accomplished the synthesis of some 1,3-
oxaphosphorinanium compounds, a new kind of hetero-
cyclic organophosphorus compounds not previously re-
ported in the literature. The relative configuration of
these compounds was established on the basis of an X-ray
diffraction study of oxide 7a. The base-induced cleavage
of compounds 3a and 3b yields oxides 7a and 7b with
complete retention of configuration at phosphorus, ster-
eochemical behavior not reported in the literature before
for these kind of compounds. We propose a mechanism
in which apical attack of the nucleophile gives phospo-
rane 8; a pseudorotation of 8 to 9 and apical departure
of the leaving group from the latter phoshorane represent
a possible pathway to explain the observed stereochem-
istry. In summary, the presence of oxygen on the six-
membered ring dramatically changes the stereochemical
course of these reactions, from complete inversion (1b and
1d) to complete retention of configuration at phosphorus
(3a and 3b). In addition, we have gained synthetic access
to these kinds of systems for future conformational
studies that we have planned.
licities proposed by Trippett,21 the methoxy group has a
strong preference to occupy an apical position since it is
the ligand bound to phosphorus with the highest relative
value.
As can be seen in Scheme 6, the two possible pathways
toward inversion of configuration require some additional
and unfavored pseudorotations. For example, conversion
of phosphoranes 8 to 10 or 9 to 11 would place the two
electronegative substituents (OH and OCH3) in equato-
rial positions and the bulky phenyl group in an apical
position (phosphoranes 10 and 11); subsequent pseu-
dorotations from 10 to 12 or from phosphoranes 11 and
13 to 12 would be again required to place the methoxy
group in an apical position prior to its elimination.
Evidence for a mechanism in which nucleophilic attack
by the OH- species occurs at phosphorus was obtained
when the reaction of 3a was carried out with NaOH
enriched with 17O (Scheme 7). The 17O NMR of the
product obtained in this reaction shows two signals, one
at +19.04 ppm corresponding to the 17O-enriched oxygen
at phosphorus of significantly higher intensity than the
other one at +29.781 ppm corresponding to the ring
oxygen (17O natural abundance), supporting the mecha-
nism shown in Scheme 6. This is in agreement with
previous results reported for 1b and 1d where no
significant attack on the methoxy carbon was observed.5
In addition, the high-resolution mass spectra shows that
the labeled 17O was incorporated in the resulting product.
Experimental Section
Synthesis of 3-Hydroxybutylphenylphosphine22 6. To
18.32 g (0.17mol) of phenylphosphine 4 dissolved in 60 mL of
anhydrous THF was added dropwise with stirring 66.7 mL of
2.5 M n-butyllithium in hexanes. The reaction was kept at 0
°C under a nitrogen atmosphere during the addition until a
yellowish precipitate was formed. The reaction mixture was
cooled to -78 °C, and an equimolar amount of 2-methyloxetane
5 (12.0 g) was added dropwise with stirring. After the addition,
the reaction mixture was allowed to come to room temperature
and then refluxed for 2 h. The reaction mixture was cooled
with an ice bath, and water was added dropwise until the
organic layer became colorless. The organic layer was removed,
(21) Trippett, S. Pure Appl. Chem. 1974, 40, 595.
(22) Issleib, K.; Roloff, H. R. Chem. Ber. 1965, 98, 2091.
J. Org. Chem, Vol. 70, No. 19, 2005 7477

Lo´pez-Cortina et al.
and the aqueous layer was extracted with diethyl ether (2 ×
150 mL). The organic layers and extracts were combined and
filtered in vacuo, and the solvents were distilled off. Distillation
in vacuo yielded 16.53 g (54%) of the desired product as a
colorless liquid, bp 119-120 °C (1 mm), and 3.47 g (11%) of
the minor isomer, 3-hydroxy-1-methyl-propylphenylphosphine,
as a colorless liquid, bp 110-115 °C (1 mm). Major Product,
°C. Anal. Calcd for C13H19O2P: C, 65.53; H, 8.04. Found: C,
65.63; H, 7.93.
Synthesis of cis- and trans-3-Methoxy-3-phenyl-2,2,6-
trimethyl-1,3-oxaphosphorinanium Tetrafluoroborate 3.
For the preparation of the trans isomer 3b, 0.05 g (0.21 mmol)
of the trans-phosphine oxide 7b was dissolved in 25 mL of dry
methylene chloride. This solution was added to a suspension
of 0.04 g (0.27 mmol) of trimethyloxonium tetrafluoroborate
in dry methylene chloride, and the resulting mixture was
stirred at room temperature for 6 h. The solution was
evaporated to dryness in vacuo to give 0.06 g (78% yield) of
the trans isomer 3b: yellow oil, 31P NMR (CDCl3) δ +69.97;
1H NMR (CDCl3) δ 1.24 (d, J ) 6.2, 3H), δ 1.24 (d, J ) 14.2,
3H), δ 1.5 (d, J ) 13.4, 3H), δ 2.94 (m, 4H), δ 4.1 (d, J ) 11.4
Hz, 3H), δ 4.28 (m, 1H), δ 7.69 (m, 5H). Anal. Calcd for C14H22-
BF4O2P: C, 49.44; H, 6.52. Found: C, 49.58; H, 6.26. The cis
isomer 3a, was prepared in a similar manner from 7a (cis
oxide); evaporation of the solvent afforded 0.05 g (71% yield)
of cis isomer 3a: yellow oil, 31P NMR (CDCl3) δ +67.27; 1H
NMR (CDCl3) δ 1.18 (d, J ) 7.0, 3H), δ 1.37 (d, J ) 16.2, 3H),
δ 1.9 (d, J ) 14, 3H), δ 3.13 (m, 4H), δ 4.1 (d, J ) 11.0 Hz,
3H), δ 4.26 (m, 1H), δ 7.88 (m, 5H). Anal. Calcd for C14H22-
BF4O2P: C, 49.44; H, 6.52. Found: C, 49.52; H, 6.37.
Base Cleavage Reaction of 3-Methoxy-r-3-phenyl-2,2,t-
6-trimethyl-1,3-oxaphosphorinanium Tetrafluoroborate
3b. To the trans-tetrafluoroborate salt 3b (0.055 g, 0.162 mmol)
was added 1 M sodium hydroxide (0.35 mL) at room temper-
ature with stirring, continuing for 1 h at room temperature,
and then heated under reflux for 2 h. The cooled reaction
mixture was extracted with methylene chloride (5 × 25 mL).
The combined extracts were dried with anhydrous sodium
sulfate, and the solvent was distilled off to give 0.035 g (91%
yield) of trans-oxide 7b previously characterized.
1
6: 31P NMR (CDCl3) δ -49.605, -49.849; H NMR (CDCl3) δ
1.130 (d, J ) 6.2 Hz, 1.5H), δ 1.134 (d, J ) 6.4 Hz, 1.5H), δ
1.58 (m, 2H), δ 1.7 (m, 2H), δ 3.3 (s, 1H), δ 3.57 (m, 1H), δ
7.27 (m, 3H), δ 7.53 (m, 2H), δ 7.42 (d, J ) 466 Hz, 1H); 13C
NMR (CDCl3) δ 23.36 (s), δ 23.42 (s), δ 26.4 (d, J ) 16.3), δ
27.7 (d, J ) 16.7), δ 31.1 (d, J ) 5.35), δ 31.2 (d, J ) 4.4), δ
67.3 (d, J ) 11.4), δ 67.6 (d, J ) 11.0), δ 129.1 (d, J ) 12.6), δ
130.1 (d, J ) 11.0), δ 132.5 (s), δ 132.73 (d, J ) 3.05). Anal.
Calcd for C10H15OP: C, 65.92; H, 8.30. Found: C, 65.70; H,
8.50. Minor Product: 31P NMR (CDCl3) δ -50.782; 1H NMR
(CDCl3) δ 0.86 (d, J ) 6.2, 1.5H), δ 0.89 (d, J ) 6.6, 1.5H), δ
1.89 (m, 3H), δ 4.05 (t, J ) 6.0, 2H), δ 7.41 (m, 3H), δ 7.7 (m,
2H), δ 7.5 (d, J ) 464, 1H).
Synthesis of 3-Oxo-3-phenyl-2,2,6-trimethyl-1,3-ox-
aphosphorinane 7. 3-Hydroxybutylphenylphosphine 6 (4 g,
0.022 mol), dissolved in 60 mL of benzene, was mixed with
32.15 mL (0.438 mol) of anhydrous reagent-grade acetone, and
then 0.189 g (1.097 mmol) of dried p-toluenesulfonic acid23 was
added. The reaction mixture was refluxed at 100 °C for 37 h
using a Dean-Stark trap. At this point, an additional portion
(21.7 mL, 0.3 mol) of acetone was added, and the reaction
mixture was kept at reflux for an additional period of 47 h.
After removal of the solvent, oxidation of the crude product
was carried out by dissolving the material in 30 mL of benzene
and adding, at 0 °C, 4.32 mL (0.02 mol) of 5.0 M tert-
butylhydroperoxide in decane.24 After the addition was com-
pleted, the reaction was allowed to come to room temperature
and was stirred overnight at this temperature. The solvent
was evaporated in vacuo and the crude product purified by
flash column (silica gel, dichloromethane/2-propanol 95/5) to
give 0.69 g (13%) of a colorless liquid corresponding to the
mixture of diastereomeric oxides of 7.
Separation of cis- and trans-3-Oxo-3-phenyl-2,2,6-tri-
methyl-1,3-oxaphosphorinanes 7a and 7b. The mixture of
phosphorinane oxides 7a and 7b obtained in the previous step
(0.5 g), was separated by chromatographic column (silica gel
230-400, acetone), affording 0.23 and 0.22 g of the isomerically
pure cis- and trans-oxides, respectively.
3-Oxo-r-3-phenyl-2,2,c-6-trimethyl-1,3-oxaphosphori-
nane 7a. 31P NMR (CDCl3) δ +27.967; 1H NMR (CDCl3) δ 1.26
(d, J ) 13.6 Hz, 3H), δ 1.29 (d, J ) 6 Hz, 3H), δ 1.70 (d, J )
11.6 Hz, 3H), δ 2.12 (m, 4H), δ 4.1 (ddq, J ) 2 Hz, J ) 11.1
Hz, J ) 6 Hz, 1H), δ 7.51 (m, 2H), δ 7.57 (m, 1H), δ 8.11 (m,
2H); 13C NMR (CDCl3) δ 20.7 (d, J ) 7.6), δ 22.4 (s), δ 24.7 (s),
δ 29.5 (d, J ) 79.31), δ 32.9 (d, J ) 6.13), δ 67.4 (d, J ) 6.13),
δ 74.6 (d, J ) 79.31), δ 128.5 (d, J ) 10.76), δ 130.3 (s), δ 131.93
(s), δ 132.38 (d, J ) 7.6); white solid, mp 102-104 °C. Anal.
Calcd for C13H19O2P: C, 65.53; H, 8.04. Found: C, 65.57; H,
7.82.
Base Cleavage Reaction of 3-Methoxy-r-3-phenyl-2,2,c-
6-trimethyl-1,3-oxaphosphorinanium Tetrafluoroborate
3a. The same procedure was followed as for the trans isomer
with similar results.
Base Cleavage Reaction of 3-Methoxy-r-3-phenyl-2,2,c-
6-trimethyl-1,3-oxaphosphorinanium Tetrafluoroborate
3a with 17O-Enriched NaOH. To the cis-tetrafluoroborate
salt 3a (0.05 g, 0. mmol) prepared as described above was
added 0.35 mL of a 1 M NaO17H solution (NaO17H was
prepared by adding 0.0078 g of Nao to 0.0065 g of 35% 17O,
H2O17) at room temperature with stirring, continuing for 1 h
at room temperature, and then heated under reflux for 2 h.
The cooled reaction mixture was extracted with methylene
chloride (5 × 25 mL). The combined extracts were dried with
anhydrous sodium sulfate, and the solvent was distilled off to
give 0.031 g (89% yield) of the 17O-enriched cis-oxide 7a. HRMS
(EI): calcd for C13H19O2P, 238.2625; found, 239.1201.
Acknowledgment. The authors wish to thank CON-
ACyT of Me´xico (44704Q) for financial support of this
work. S.T.L.C. also wishes to thank CONACyT for a
Graduate Scholarship (117160). We are also indebted
to Dr. Ba´rbara Gordillo (Department of Chemistry,
CINVESTAV, Me´xico) and Dr. Jorge Guerrero (CIQ-
UAEM, Mexico) for their valuable technical help with
some of the NMR experiments carried out on some of
these compounds.
3-Oxo-r-3-phenyl-2,2,t-6-trimethyl-1,3-oxaphosphori-
nane 7b: 31P NMR (CDCl3) δ +28.266; 1H NMR (CDCl3) δ 1.28
(d, J ) 6 Hz, 3H), δ 1.27 (d, J ) 13.6 Hz, 3H), δ 1.38 (d, J )
12 Hz, 3H), δ 2.22 (m, 4H), δ 4.0 (ddq, J ) 2 Hz, J ) 11 Hz,
J ) 6 Hz, 1H), δ 7.48 (m, 2H), δ 7.55 (m, 1H), δ 7.78 (m, 2H);
13C NMR (CDCl3) δ 20.7 (d, J ) 5.4), δ 22.2 (s), δ 23.7 (s), δ
28.9 (d, J ) 6.13), δ 29.9 (d, J ) 70.2), δ 68.1 (d, J ) 4.62), δ
74.9 (d, J ) 76.30), δ 128.7 (d, J ) 12.16), δ 130.5 (s), δ 131.5
(d, J ) 9.15), δ 132.2 (d, J ) 3.11); white solid, mp 112-115
Supporting Information Available: General information
for compounds 3a,b, 6, and 7a,b and crystallographic data for
compound 7a (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(23) Purification of Laboratory Chemicals, 3rd. ed; Perrin, D. D.,
Armarego, W. L. F., Eds.; Pergamon Press: 1989.
(24) Denney, D. B.; Hanifin, J. W., Jr. Tetrahedron Lett. 1963, 2177.
JO050901W
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