Stereochemistry of base-induced cleavage of methoxide ion on cis- and trans-1,4-diphenylphosphorinanium salts. A different behavior with a phenyl substituent

Article abstract of DOI:10.1016/j.tet.2010.05.095

The synthesis and characterization of pure cis- and trans-1,4-diphenyl-1- methoxy-phosphorinanium tetrafluoroborate salts 11a and 11b, molecules designed to evaluate the effect of a phenyl substituent at C-4 on the stereochemical course of base-induced nu

Full text of DOI:10.1016/j.tet.2010.05.095

Tetrahedron 66 (2010) 6188e6194
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Tetrahedron
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Stereochemistry of base-induced cleavage of methoxide ion
on cis- and trans-1,4-diphenylphosphorinanium salts. A different
behavior with a phenyl substituent
Susana López-Cortina a, Araceli Medina-Arreguin b, Eugenio Hernández-Fernández a, Sylvain Bernès a,
,
Jorge Guerrero-Alvarez b, Mario Ordoñez b, Mario Fernández-Zertuche b
*
a Facultad de Ciencias Químicas, Universidad Autónoma de Nuevo León, Av., Universidad s/n, Cd. Universitaria, 66451 San Nicolás de los Garza, Nuevo León, México
b Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa 62209, Cuernavaca, Morelos, México
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and characterization of pure cis- and trans-1,4-diphenyl-1-methoxy-phosphorinanium tetra-
fluoroborate salts 11a and 11b, molecules designed to evaluate the effect of a phenyl substituent at C-4 on the
stereochemical course of base-induced nucleophilic displacement of the methoxy group at phosphorus, was
accomplished. The presence of a phenyl substituent at C-4 changes the stereochemical course of these re-
actions, from complete inversion with alkyl groups to products where retention of configuration at phos-
phorus predominates. We suggest a mechanism involving Berry pseudorotations and provide evidence that
the hydroxide ion attacks the phosphorus atom through experiments with NaOH enriched with 17O.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 31 March 2010
Received in revised form 21 May 2010
Accepted 24 May 2010
Available online 31 May 2010
Keywords:
Phosphorinanium salts
Phosphine oxides
Phosphorus stereochemistry
Berry psuedorotations
1. Introduction
reaction with base is non-stereospecific yielding phosphine oxides as
mixtures of different proportions.8 However, when the more elec-
Phosphorus-containing compounds and their chemistry have
gained considerable attention as a result of their biological1 and
chemical profiles.2 The most frequently encountered reactions in
phosphorus chemistry are nucleophilic substitutions; such reactions
at tetravalent phosphorus centers are involved in a number of cel-
lular energetic and biosynthesis processes.3 In this context, quater-
nary phosphonium salts undergo nucleophilic displacement
reactions induced by aqueous hydroxide ion to yield phosphine
oxides4 and with few exceptions, these reactions have shown in-
version of configuration at phosphorus as the stereochemical
course.5 In cyclic phosphonium salts, however, the stereochemical
behavior is much more complex as ring size has a strong effect on the
stereochemical course of these reactions. For example, phospheta-
niumsalts6 formthecorresponding phosphineoxides withcomplete
retention of configuration at phosphorus, whereas phospholanium
salts, depending on the specific compounds, react with base to give
products with complete retention of configuration at phosphorus or
as a mixture of stereoisomers.7 Both mechanistic and stereochemical
arguments have been suggested to explain these differences.
tronegative methoxy group is used as the leaving group, pure sam-
ples of cis and trans 4-methyl (1a and 1b) or 4-tert-butyl (3a and 3b)
afford the corresponding phosphine oxides 2 or 4 (Scheme 1) with
complete inversion of configuration at phosphorus.9
R
R
NaOH (1M)
PF6 100% inversion
-
P
P
Ph
Ph
OCH3
O
1a R= CH3
3a R= t-Bu
2b R= CH3
4b R= t-Bu
R
R
NaOH (1M)
PF6 100% inversion
-
P
P
In six-membered rings the most studied leaving groups have
been the benzyl and the methoxy groups attached to the phosphorus
atom. When the benzyl group is used as the leaving group, the
Ph
Ph
O
OCH3
1b R= CH3
3b R= t-Bu
2a R= CH3
4a R= t-Bu
Scheme 1. Stereochemical behavior of phosphorinanium salts.
* Corresponding author. E-mail address: mfz@uaem.mx (M. Fernández-Zertuche).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.095

S. López-Cortina et al. / Tetrahedron 66 (2010) 6188e6194
6189
We have recently reported our results on the hydroxide-induced
displacement of the methoxy groups on samples of pure cis and
trans isomers of 3-methoxy-2,2,6-trimethyl-3-phenyl-1,3-oxa-
phosphorinanium tetrafluoroborate salts 5a and 5b (Scheme 2),
systems designed to study the effect of a second heteroatom in the
ring system on the stereochemistry of the reaction. In our study, the
presence of the oxygen atom induces a different stereochemical
outcome since 5a and 5b reacted with base to yield the phosphine
oxides 6a and 6b with complete retention of configuration at
phosphorus.10 This study contrasts with the results observed in
five-membered rings where the presence of the oxygen has no
effect on the stereochemistry of the reaction.11
Cremer et al.12 Reduction of dimethyl 3-phenylglutarate 713 with
lithium aluminum hydride in THF, followed by treatment of the
resulting diol with phosphorus tribromide, afforded 8 in 92% yield.
The phosphorinanium bromide 9 was prepared in 56% yield by
heating 8 with diphenyl(trimethylsilyl)phosphine14 in toluene for
12 h. Subsequent treatment of salt 9 under aqueous sodium hy-
droxide afforded the phosphine oxides 10 as a 70:30 diastereomeric
mixture (31P NMR).
The separation of the diastereomeric mixture of phosphine
oxides 10 was accomplished by column chromatography leading to
10a and 10b in a very pure form (Scheme 4). Both compounds were
CH3
O
CH3
Ph
O
NaOH (1M)
100% retention
CH3
CH3
CH3
CH3
-
BF4
P
P
P
Ph
Ph
Ph
OCH3
O
Ph
O
Ph
P
O
10
5a
6a
cis-10a
CH3
O
CH3
Column Chromatography
Silica gel (230-400)
CH2Cl2/i-PrOH (95:5)
Ph
O
NaOH (1M)
CH3
CH3
CH3
CH3
-
Ph
100% retention
BF4
P
P
Ph
O
OCH3
P
5b
6b
Ph
O
Scheme 2. Stereochemical behavior of 1,3-oxaphosphorinanes.
trans-10b
Scheme 4. Diastereomeric separation of phosphine oxides 10a and 10b.
As part of a series of studies designed to study the effect of
different structural variants on the stereochemistry of nucleophilic
displacement reactions of the methoxy group in phosphorinanium
salts, we herein report our results on the base-induced displace-
ment of the methoxy groups from cis and trans 1,4-diphenylphos-
phorinanium tetrafluoroborate salts 11a and 11b in order to assess
the effect of a phenyl substituent at C-4 on these cyclic systems.
Whereas the effect of alkyl substituents at C-4 in phosphorinanium
salts is well documented, the effect of aromatic substituents in the
stereochemical course of these reactions has remained unexplored
to date.
fully characterized by NMR spectroscopy; however, in order to
carry out the stereochemical study, it was necessary to establish the
relative stereochemistry of these compounds. The assignment of
the relative configurations of diastereoisomers 10a and 10b were
unambiguously established by X-ray crystal structure de-
terminations on both.15 Figure 1 shows the X-ray crystal structure
2. Results and discussion
The synthesis of the 1,4-diphenylphosphorinane oxides 10,
which are the key precursors to our objective molecules, is outlined
in Scheme 3 and is adapted from a similar procedure reported by
Br
1) LiAlH4,THF
CO2Me
2) PBr3
Ph
Ph
CO2Me
92%
Br
8
7
Ph2PSiMe3
Toluene
56%
Ph
Ph
NaOH(aq) 20%
95%
Figure 1. The molecular structure of one of the two independent molecules in 10a,
with displacement ellipsoids shown at the 30% probability level for non-H atoms. The
inset is an overlay between the two independent molecules.
P
Br-
P
Ph
O
Ph Ph
of 10a (cis isomer) and Figure 2 of 10b (trans isomer). cis/trans
Nomenclature is used in this work to denote the disposition of the
phenyl groups at P and C-4.16,17
10
9
Scheme 3. Preparation of 1,4-diphenylphosphorinane oxides.

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S. López-Cortina et al. / Tetrahedron 66 (2010) 6188e6194
containing heterocycles and/or C2-subtituted phosphorinane de-
rivatives, for which an axial phenyl substituent may be found in
a bisecting orientation.10
A very different picture is observed for stereoisomer 10b. The
most differentiating feature is related to space group symmetry.
Isomer 10a belongs to a centrosymmetric space group while
crystals of 10b clearly lack inversion symmetry. As a consequence,
the asymmetric unit for the trans isomer is duplicated compared
to the 10a. Four independent molecules are thus found in 10b,
which potentially correspond to four conformers. The substitution
of the phosphorinane ring is identical for all the four molecules,
with phenyl rings now placed in equatorial positions (Fig. 2).
Unexpectedly, the phenyl at C-4 is twisted from the bisecting
orientation observed in 10a. The degree of rotational freedom
about the Cephenyl bonds can be roughly measured by comput-
Figure 2. The molecular structure of one of the four independent molecules in 10b,
with displacement ellipsoids shown at the 30% probability level for non-H atoms. The
inset is an overlay between the four independent molecules.17
ing the angle
D between the phenyl plane and the P1/O1/C4 mean
plane, corresponding to the phosphorinane mirror plane in an
ideal chair geometry: the bisecting conformer is characterized by
Compound 10a (Fig. 1) is stabilized in the solid-state with the
expected chair conformation for the core phosphorinane ring, with
phenyl substituents at P and C-4 atoms placed in axial and equa-
torial positions, respectively. The asymmetric unit contains two
independent molecules and one lattice water molecule, affording
a hemihydrate. The water molecule stabilizes the crystal structure,
D
¼0, while the perpendicular conformer is defined by
D
¼90ꢀ. The
phenyl group at C-4 is clearly bisecting the phosphorinane cycle in
10a, while analogous
D
angles range from 22.1(3)ꢀ to 42.7(2)ꢀ in
10b (Table 1). Regarding the equatorial phenyl bonded to the P
atom, the four molecules display two totally different conforma-
Table 1
Rotational parameters for the conformation of the phenyl rings with respect to the phosphorinane chair in 10a and 10b
10a
10b
Molecule P1
D1¼73.39 (7)
D2¼1.83 (14)
D1¼72.72 (12)
D2¼1.9 (2)
Molecule P1
D1¼87.5 (2)
D2¼22.1 (3)
D1¼4.1 (4)
D2¼42.7 (2)
Molecule P4
Molecule P3
D1¼78.5 (2)
D2¼39.0 (2)
D1¼1.1 (4)
D2¼26.0 (2)
Molecule P2
Molecule P2
Dihedral angles (ꢀ) between planes: D1¼angle (p1
ring defined by atoms P, O, C4.
,
pm); D2¼angle (p2
, pm); where p1 and p1 are mean planes for phenyl rings and pm is the mirror plane of the phosphorinane
by bridging molecules P1 through strong OeH/O hydrogen bonds
involving P]O groups as acceptors.
tions: two molecules have the phenyl in an orientation close to
perpendicular, while the others include bisecting phenyl groups
(Fig. 2, inset).
Molecular conformations may be compared for independent
molecules, assuming a rigid phosphorinane ring. A fit18 between
both molecules shows that the phenyl substituting the P atom has
a single orientation with respect to the phosphorinane core, while
the phenyl group at C-4 experiments small libration motions, albeit
limited to ca. 6ꢀ (Fig. 1, inset). Both molecules thus display almost
identical conformations in the solid-state, and the crystallization
with two crystallographically independent molecules is likely to be
a consequence of inclusion of water in the lattice rather than a re-
flection of conformational flexibility. The bisected conformation
about the C-4-phenyl bond is the same as that of 1,4-diphenyl-cy-
clohexane19 and other related systems, and has been shown from
density functional calculations to be the expected conformation for
an equatorial phenyl group substituting a rigid six-membered
ring.20 In contrast, the axial phenyl group at the phosphorus atom is
perpendicular to the mirror plane of the phosphorinane ring. Such
an orientation avoids 1,3-syn diaxial repulsion between the phenyl
ortho H atoms and the phosphorinane ring H atoms, a situation
reminiscent of that described for non-sterically hindered eq-phe-
nyl-cyclohexane derivatives.21 It is worth mentioning that the same
orientation was described in the X-ray study of 4-tert-butyl-1-
phenylphosphorinane-1-sulfide,22 suggesting that the stabilized
conformation is mainly imposed by minimization of 1,3-syn diaxial
interactions. This rule is obviously relaxed in the case of O/S-
It is clear, from this conformational description, that 10b is
a more flexible molecule than 10a. Although transferring this
behavior for the isomers in solution is not possible, one might
genuinely expect that equatorial phenyl rings in 10b are almost
free to rotate, while 10a should be restricted to few rotational
conformers.
In addition to the X-ray studies, the 31P NMR of these com-
pounds supports the stereochemical assignments given to 10a and
10b. Comparison of their chemical shifts shows that the phospho-
rus signal for 10a appears at þ35.11 ppm and that for 10b at
þ31.16 ppm. This is consistent with the fact that when the oxygen
occupies an axial position as in 10b, the 31P NMR shows an upfield
signal and a downfield resonance when it occupies an equatorial
position.23
Once the configurations of the phosphine oxides 10a and 10b
were established, the required molecules for our study 11a and 11b
were obtained by direct methylation of 10a and 10b with trime-
thyloxonium tetrafluoroborate. The configuration of 11a and 11b
was assumed to be the same on the basis of the established con-
figurations of their parents 10a and 10b, respectively, and the
known fact that methylation of cyclic phosphine oxides with this
reagent proceeds with retention of configuration at phosphorus
(Scheme 5).24 Some key NMR signals were used for the structural

S. López-Cortina et al. / Tetrahedron 66 (2010) 6188e6194
6191
relative preference of a substituent to occupy the apical or equa-
torial site in the more commonly observed trigonal bipyramid (TBP)
geometry, has been a subject of intensive studies in the past.26 In
spite of the preference of the phosphorinane ring to occupy equa-
torial-equatorial disposition in SN2(P) mechanism, in order to ex-
plain inversion of configuration at phosphorus in phosphorinane
ring systems substituted with Me or t-Bu groups at C-4, the non-
stereospecific behavior observed in our study led us to propose that
the influence of the phenyl group at C-4 on the phosphorinane ring
favors a notable preference to occupy apical-equatorial disposition
even in the case of an electronegative methoxy leaving group. This
could be supported by the general statement in which four- to
seven-membered rings at phosphorus prefer an apical-equatorial
disposition unless constrained by fused rings. This behavior must
be taken into an account to explain the observed stereochemistry in
the studied phosphorus displacement reactions.
Ph
P
Ph
-
(CH3)3O+BF4
-
CH2Cl2
83%
BF4
OCH3
P
Ph
Ph
O
10a
11a
Ph
Ph
(CH3)3O+BF4
-
-
BF4
OCH3
11b
CH2Cl2
80%
P
P
Ph
10b
Ph
O
Scheme 5. Preparation of 1,4-diphenylphosphorinanium salts.
On the basis of the latter and on the different mechanisms that
have been proposed in the literature for the nucleophilic sub-
stitution at phosphorus in cyclic compounds, the reaction mecha-
nism that best explains the observed stereochemical behavior is the
one involving Berry pseudorotation of phosphoranes.27 This
mechanism implies the initial formation of a phosphorane from an
apical attack of a hydroxide ion on the phosphorus atom resulting
in an apical-equatorial disposition of the phosphorinane ring.
The pathway toward retention (Scheme 7) of configuration an-
alyzing the behavior of 11b, involves the initial formation of
phosphorane 17 by an apical attack of the hydroxide ion at phos-
phorus atom.28 Only one pseudorotation toward phosphorane 16
places the methoxy leaving group in an apical position, leading to
the oxide 10a with retention of configuration after the base-in-
duced elimination of this group. The extended principle of micro-
scopic reversibility supports the assumption of apical attack and
apical departure, and establishes that apical bonds are longer and
weaker. In addition, 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 of apicophilicity according to Trip-
pett’s scale.29 On the other hand, phosphoranes 17 and 16 both have
a trans disposition of the phenyl groups, a condition considered
favorable to avoid steric hindrance between these groups through
the mechanistic pathway. The two possible pathways toward in-
version of configuration, oxide 10a, involve the formation of unfa-
vored phosphoranes 14 or 15 placing the two electronegative
substituents (OH and OCH3) in equatorial positions and the bulky
phenyl group in an apical site. According to Bent’s rule,30 these
phosphoranes would be required to place the methoxy group in
apical position prior to its elimination (from 14 to 13 or from 15 and
12 to 13); to achieve this condition, this would require additional
pseudorotations, as compared to the favored retention pathway.
As can be seen in Scheme 7, the mechanistic pathway proposed
to explain the stereochemical behavior of 11a toward retention and
inversion products, implies similar considerations as previously
described for 11b; however, the difference in the retention/in-
version ratio suggests that the influence of the phenyl group at C-4
must be taken into an account. The comparison of phosphoranes
involved in the retention pathways of both salts, led us to propose
that the trans disposition of the phenyl groups in phosphoranes 17
and 16 avoids unfavorable interactions between them, interactions
that could not be completely avoided in a cis disposition of the
phenyl groups, phosphoranes 13 and 14, and consequently having
a higher net retention for 11b than for 11a.
determination of these compounds. For example, the signals for the
methoxy groups on both isomers appear as doublets centered
around 3.9 ppm as a result of the coupling of these protons with the
adjacent phosphorus atom. Thus the 3JPeH(OCH3) coupling constants
have identical values of 12.6 Hz and are in agreement with those
reported by Marsi9 for phosphorus cyclic compounds substituted
with methoxy groups. In addition, the 31P NMR signals for each
isomer appear at þ79.05 ppm for 11a and þ79.44 ppm for 11b.
The nucleophilic displacement reactions in aqueous sodium
hydroxide carried out in salts 11a and 11b (Scheme 6) led to the
Ph
Ph
Ph
NaOH (1M)
+
+
-
BF4
P
P
P
Ph
Ph
Ph
OCH3
O
O
11a
10a
62%
Ph
10b
38%
Ph
Ph
NaOH (1M)
-
BF4
OCH3
11b
P
P
P
Ph
10a
Ph
Ph
O
O
10b
25%
75%
Scheme 6. Stereochemical behavior of 11a and 11b.
formation of mixtures of the phosphine oxides 10a and 10b in
which the products of retention of configuration at phosphorus
predominate. Specifically, salt 11a yields 62% of the retention
product 10a and 38% of the inversion product 10b, whereas salt 11b
affords 75% of the retention product 10b and 25% of the inversion
product 10a. The stereochemistry observed could be easily cor-
roborated by direct comparison of the 1H and 31P NMR spectra of
the isolated phosphine oxides previously used for the synthesis of
11a and 11b since they are exactly the same compounds. In addi-
tion, the diastereomeric ratios of these products were determined
by 31P NMR data of the crude reaction mixtures.25
The stereochemical behavior observed in our study dramatically
contrasts with the stereochemical behavior reported by Marsi9 in
phosphorinane ring systems substituted with alkyl groups at C-4
where the base-induced displacement of a methoxy group pro-
ceeds with complete inversion of configuration at phosphorus,
a behavior explained on the basis of the SN2(P) mechanism. The
Finally, evidence for a mechanism in which nucleophilic attack
by the hydroxide ion occurs at phosphorus was obtained when the
reaction of 12b was carried out with NaOH enriched with 17O
(Scheme 8). The 17O NMR of the products obtained in this reaction
shows two signals, one at þ28.06 ppm and another one at
þ55.44 ppm. This evidence supports the mechanism shown in

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S. López-Cortina et al. / Tetrahedron 66 (2010) 6188e6194
Ph
P
Ph
10a
O
-
OH
Ph
P
Ph
Ph
Ph
-
OH
Ph
OH
OCH
Ph
OH
OCH
P
-
P
P
Ph
BF
OCH
OH
Ph
OCH
11a
14
12
13
Ph
Ph
Ph
Ph
OH
OCH
Ph
OH
OCH
P
OCH
P
Ph
P
OH
15
16
17
-
-
OH
OH
Ph
Ph
-
BF
P
P
Ph
10b
Ph
11b
O
OCH
Scheme 7. Proposed mechanism to stereochemical outcome.
group was obtained by the reaction of 12b with NaOH enriched with
17O, 17O NMR, and high resolution mass spectra showed that the
labeled 17O was incorporated in the resulting products.
In summary, the presence of the phenyl substituent at C-4 on
11a and 11b changes the stereochemical course of these reactions,
from complete inversion in systems substituted with alkyl groups,
such as 1a,b and 3a,b to products where retention of configuration
at phosphorus predominates.
Ph
P
Ph
P
17O
11a,b
Na17OH (1M)
-
BF4
Ph
OCH3
Ph
12b
Scheme 8. Reaction with Na17OH.
4. Experimental section
Scheme 7 and is in agreement with other studies reported in the
literature where no significant attack on the methoxy carbon was
observed.9,10 In addition, the high resolution mass spectra shows
that the labeled 17O was incorporated in the resulting products.
4.1. General experimental methods
1H NMR spectra were recorded at 400 MHz with CDCl3 as sol-
vent and tetramethylsilane as internal standard. 13C NMR spectra
were recorded at 100 MHz with CDCl3 as solvent. 31P NMR spectra
were recorded at 81 MHz with CDCl3 as solvent and 85% H3PO4 as
external standard. THF was dried by distillation over sodium ben-
zophenone ketyl. All other solvents were used after distillation at
normal pressure.
3. Conclusions
In this work, we have accomplished the synthesis of cis- and
trans-1-methoxy-1,4-diphenylphosphorinanium tetrafluoroborate
salts 11a and 11b, heterocyclic organophosphorus compounds not
previously reported in the literature. The base-induced cleavage of
these compounds results in the formation of phosphine oxides 10a
and 10b where the products with retention of configuration at
phosphorus tend to predominate. The relative configuration of 10a
and 10b was established by X-ray diffraction studies. We suggested
a mechanism involving Berry pseudorotations on phosphoranes 12
and 17 formed after apical attack of a hydroxide ion on the phos-
phorus atom resulting in an apical-equatorial disposition of the
phosphorinane ring system. Subsequent apical departure of the
leaving group from 13 or 16 leads mainly to products where re-
tention of configuration at phosphorus predominates. Evidence that
thehydroxide ion attacks phosphorus and not carbon of themethoxy
4.1.1. 3-Phenyl-1,5-dibromopentane (8). Exactly 0.408 g (10.8 mmol)
of lithium aluminum hydride were suspended in 8.0 mL of anhy-
drous THF at 0 ꢀC. To this suspension was added dropwise a solution
of 2.0 g (8.5 mmol) of dimethyl 3-phenylglutarate dissolved in
10.0 mL of THF. When the addition was completed, the resulting
mixture was refluxed for 1.5 h period. The reaction mixture was
allowed to cool to room temperature, and distilled water was added
very slowly until the evolution of gas ceased; then, 10.0 mL of a 20%
solution of hydrochloric acid were added. The reaction mixture was
extracted with dichloromethane, the organic layers were combined
and dried over sodium sulfate and the solvent removed under vac-
cuo to produce 1.43 g (94%) of the product as a yellow oil, which was

S. López-Cortina et al. / Tetrahedron 66 (2010) 6188e6194
6193
immediately treated with 2.9 g (10.6 mmol, 1.0 mL) of phosphorus
tribromide at 0 ꢀC. When the addition was completed, the ice bath
was removed and the reaction mixture was stirred overnight at
room temperature. The resulting mixture was treated with 30.0 mL
of distilled water and the reddish solid formed removed by filtration.
The filtrate was extracted with dichloromethane, the organic layers
were combined, dried over anhydrous sodium sulfate, and the sol-
phosphine oxide 10a were dissolved in 25.0 mL of dichloro-
methane. To this solution was added solution of 0.26 g
a
(1.77 mmol) of trimethyloxonium tetrafluoroborate in 25.0 mL of
dichloromethane, and the resulting mixture was stirred at room
temperature under nitrogen for 6 h. When the reaction was com-
pleted, the solvent was evaporated and 0.33 g (83%) of the product
11a were isolated as a white solid, mp 100e102 ꢀC. 1H NMR (CDCl3,
vent evaporated to give 2.37 g (98%) of 8 as a colorless oil. 1H NMR
200 MHz) d 1.78 (m, 4H, H2,6), 2.11(m, 4H, H3,5), 2.75e3.14 (m, 1H,
3
(CDCl3, 400 MHz)
d
2.2 (m, 4H, H2,4
,
3JH2,4-H3¼8.0, JH2,4-H1,5¼6.0),
H4, 3JH4eH3,5¼12.6), 3.91 (d, 3H, OCH3, 3JOCH3eP¼12.6), 7.06e7.12 (m,
3.0e3.1 (m, 3H, H1,3), 3.2e3.3 (m, 2H, H5), 7.2e7.4 (m, 5H, Harom); 13
C
2H, Harom), 7.17e7.29 (m, 3H, Harom), 7.66e8.08(m, 5H, Harom); 31P
NMR (CDCl3,100 MHz)
(s, Cpara), 127.8 (s, Cortho), 129.0 (s, Cmeta), 141.5 (s, Cipso). HRMS (EI)
calcd for C11H14Br2: 306.0369; found: 305.9445.
d
31.7 (s, C2,4), 39.4 (s, C1,5), 42.9 (s, C3), 127.2
NMR(CDCl3, 81 MHz)
372.1395; found: 372.1419. Compound 11b was obtained in a simi-
d
þ79.05. HRMS (EI) calcd for C18H22BF4OP:
lar manner yielding 0.23 g (80%) of the product as a white solid, mp
148e150 ꢀC. 1H NMR (CDCl3, 200 MHz)
d 1.14e1.30 (m, 2H, H2,6ax,
4.1.2. 1,1,4-Triphenylphosphorinanium bromide (9). A mixture of
2.37 g (7.70 mmol) of 3-phenyl-1,5-dibromopentane and 1.37 mL
(10.2 mmol) of trimethylsilyl (diphenylphosphine) in 25.0 mL of
anhydrous toluene was heated under reflux for 30 h period. The
mixture was cooled to room temperature, and the white precipitate
formed was collected by filtration, the process yielded 1.78 g (56%)
of 9 as a white solid, mp 174e176 ꢀC. 1H NMR (CD3OD, 400 MHz)
3JH2,6axeH3,5ax¼15.0), 2.00e2.30 (m, 4H, H2,6,3,5eq), 2.35e2.60 (m,
3
2H, H3,5ax), 2.78e2.81 (m, 1H, H4, JH4eH3,5ax¼15.0), 3.88 (d, 3H,
3
OCH3, JOCH3eP¼12.6), 7.18e7.40 (m, 5H, Harom), 7.43e7.75 (m, 3H,
Harom), 7.80e8.00 (m, 2H, Harom); 31P NMR (CDCl3, 81 MHz)
d
þ79.44. HRMS (EI) calcd for C18H22BF4OP: 372.1395; found:
372.1403.
d
1.86e1.98 (m, 2H, H2,6), 2.38e2.50 (dd, 2H, H2,6, 3JH2,6-H3,5¼15.0),
4.1.5. Base-induced substitution reaction of 1-methoxy-cis-1,4-di-
phenylphosphorinanium
3
3.10e3.20 (m, 3H, H3,5,4), 3.46e3.53 (t, 2H, H3,5 JH3,5eH2,6¼15.0),
7.14e7.30 (m, 5H, Harom), 7.66e7.97 (m, 8H, Harom), 8.15e8.20
tetrafluoroborate
(11a). To
0.30 g
(0.81 mmol) of salt 11a was added a 1.0 M solution of sodium hy-
droxide at room temperature. The mixture was stirred at room
temperature for 1 h and then refluxed for an additional 2 h. The
mixture was allowed to cool to room temperature and then
extracted with dichloromethane. The organic layers were com-
bined, dried over sodium sulfate and the solvent evaporated to
yield 0.19 g of a mixture of the corresponding phosphorinane
oxides. Analysis of the 31P NMR signals of the mixture showed 62%
of 10a and 38% of 10b, both compounds previously characterized.
The same procedure was used as for the reaction of the 11b isomer
with similar results, yielding 0.12 g of a mixture of the corre-
sponding phosphorinane oxides. Analysis of the 31P NMR signals of
the mixture showed a 75% of 10b and 25% of 10a, both compounds
previously characterized.
(m, 2H, Harom); 13C NMR (CD3OD, 100 MHz)
d 20.21 (d, C2,6,
1JC2,6eP¼50.1), 30.11 (d, C3,5, 2JC3,5eP¼6.1), 43.65 (d, C4, 3JC4eP¼6.1),
127.61 (s, Cortho), 128.10 (s, Cmeta), 129.86 (s, Cpara), 131.30 (d, Cortho
,
,
2JCeP¼12.2), 132.05 (d, Cmeta
,
3JCmetaeP¼12.2), 132.94 (d, Cpara
4JCparaeP¼10.6), 136.12 (d, Cipso, 1JCipsoeP¼45.6), 145.60 (s, Cipso); 31P
NMR (CD3OD, 81 MHz)
d
þ29.4. HRMS (EI) calcd for C23H24BrP:
411.3212; found: 411.3372.
4.1.3. 1-Oxo-1,4-diphenylphosphorinane(10). Exactly 1.7 g (4.13
mmol) of the bromide phosphorinanium salt 9 and 15.0 mL of
a 20% solution of sodium hydroxide were heated under reflux
overnight. The reaction mixture was allowed to cool to room
temperature and was extracted with dichloromethane; the com-
bined organic layers were dried over sodium sulfate and the solvent
evaporated to afford 1.2 g (95%) as a 70:30 isomeric mixture of the
4.1.6. Base substitution reaction of 1-methoxy-trans-1,4-diphenyl-
phosphorinanium 11b with 17O-enriched sodium hydroxide. Exactly
0.03 mL of a 1.0 M solution of Na17OH (prepared by adding 7.00 mg
of Naꢀ to 6.0 mg of 35% H217O) was added to 0.047 g (0.125 mmol) of
salt 11b as previously described for base-induced substitution re-
actions of 11a and 11b. The reaction was finished and 0.024 g (71%)
product. 31P NMR (CDCl3):
d
þ34.1,
d
þ31.1. The diastereomeric
mixture of 10a and 10b were separated through a chromatographic
column (silica gel) using a 95:5 mixture of dichloromethane/iso-
propanol as eluent. Compound (10a): 0.62 g (52%), mp 125e127 ꢀC.
1H NMR (CDCl3, 400 MHz)
d 1.70e1.85 (m, 2H, H3,5ax), 2.14e2.42 (m,
4H, H3,5,2,6eq), 2.67 (dd, 2H, H2,6ax, 3JH2,6ax-3,5ax¼15.6), 2.82 (dd, 1H,
4ax, 3JH4axeH3,5ax¼11.6), 7.09e7.12 (m, 1H, H16para), 7.17e7.29 (m, 4H,
H14,18ortho, H15,17meta), 7.55e7.62 (m, 3H, H8,12ortho, H10para), 7.80e7.85
of the 17O-enriched oxide products 10a and 10b were obtained. 17
O
NMR (CDCl3, 40 MHz)
d 28.08, d 55.44. HRMS (EI) calcd for
C17H1917OP: 271.1248; found: 271.1285.
(m, 2H, H9,11meta); 13C NMR (CDCl3 100 MHz)
d 26.9 (d, C2,6,
1JCeP¼63.5), 31.1 (d, C3,5
,
2JCeP¼3.0), 43.7 (d, C4, JCeP¼6.0), 126.7
3
Acknowledgements
(s, C16para), 126.9 (s, C14,18ortho), 128.8 (s, C9,11,15,17meta), 129.5 (d,
C8,12ortho
,
2JCeP¼11.0), 130.2 (d, C7ipso,1JCeP¼9.0), 132.6 (s, C10para),
The authors thank CONACyT of México (82129) for financial
support of this work. Araceli Medina Arreguin thanks PROMEP
(UAEMOR-CA-33) for a Graduate Scholarship. Susana López Cortina
thanks Karla Treviño Romero for her technical help in some syn-
thetic experiments.
144.7 (s, C13ipso); 31P NMR (CDCl3, 81 MHz)
d
þ34.60. Anal. Calcd for
C17H19OP: C, 75.53; H, 7.08. Found: C, 75.81; H, 7.17. Compound
(10b): 0.41 g (35%), mp 183e186 ꢀC. 1H NMR (CDCl3, 400 MHz)
d
1.95e2.06 (m, 2H, H2,6ax), 2.10e2.30 (m, 4H, H2,6,3,5eq), 2.38e2.51
3
(m, 2H, H3,5ax), 2.74 (dd, 1H, H4, JH4axeH3,5ax¼12.0), 7.20e7.36
(m, 5H, H14,18ortho, H16para, H15,17meta,), 7.50e7.60 (m, 3H, H8,12ortho,
Supplementary data
H10para), 7.70e7.90 (m, 2H, H9,11meta); 13C NMR (CDCl3, 400 MHz)
1
d
28.35 (d, C2,6, JCeP¼65.3), 28.95 (d,C3,5
,
2JCeP¼4.5), 45.26 (s, C4),
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.05.095.
126.79 (s, C16para), 126.86 (s, C14,18ortho), 128.78 (s, C9,11,15,17meta),
2
1
128.90 (d, C8,12ortho JCeP¼12.1), 130.34 (d, C7ipso JCeP¼36.4), 132.39
(s, C10para), 145.58 (s, C13ipso); 31P NMR (CDCl3, 81 MHz)
d
þ31.99.
References and notes
Anal. Calcd for C17H19OP: C, 75.53; H, 7.08. Found: C, 75.77, H, 7.11.
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