Synthesis of 2,3-dihydro-1-phenylbenzo[b]phosphole (1-phenylphosphindane) and its use as a mechanistic test in the asymmetric appel reaction: Decisive evidence against involvement of pseudorotation in the stereoselecting step

Article abstract of DOI:10.1021/jo401318g

Racemic 2,3-dihydro-1-phenylbenzo[b]phosphole was obtained by reduction of 1-phenylbenzo[b]phosphole-1-oxide, itself derived by ring-closing metathesis of phenylstyrylvinylphosphine oxide. The title compound was then reoxidized under asymmetric Appel cond

Full text of DOI:10.1021/jo401318g

Note
pubs.acs.org/joc
Synthesis of 2,3-Dihydro-1-phenylbenzo[b]phosphole
(1‑Phenylphosphindane) and Its Use as a Mechanistic Test in the
Asymmetric Appel Reaction: Decisive Evidence against Involvement
of Pseudorotation in the Stereoselecting Step
Damien J. Carr, Jaya Satyanarayana Kudavalli, Katherine S. Dunne, Helge Muller-Bunz,
̈
and Declan G. Gilheany*
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
S
* Supporting Information
ABSTRACT: Racemic 2,3-dihydro-1-phenylbenzo[b]-
phosphole was obtained by reduction of 1-phenylbenzo[b]-
phosphole-1-oxide, itself derived by ring-closing metathesis of
phenylstyrylvinylphosphine oxide. The title compound was
then reoxidized under asymmetric Appel conditions. Compar-
ison of the sense and degree of the stereoselectivity to those obtained with an open-chain analogue indicated that the ring system
does not affect the selectivity of the process. This in turn strongly suggests that the stereoselection is not related to
pseudorotamer preferences in putative phosphorane intermediates.
entacoordinate phosphorus intermediates play an impor-
tant role in synthetically valuable transformations such as
arylmethylphenylphosphines.11,14 It involves the transient
generation of an intermediate chlorophosphonium salt (CPS)
(δP ≈ 70−75 ppm) and trapping by the alcohol (R*OH) to
give unequal amounts of a pair of diastereomeric alkoxyphos-
phonium salts (DAPS) (δP ≈ 65−70 ppm), which then
undergo slow Arbuzov collapse to form scalemic phosphine
oxide.
The likely routes for the source of the stereoselection in the
conversion of CPS to DAPS are shown in Scheme 2 along with
their required relative rates. Pathway A posits the formation of
diastereomeric pentacoordinate alkoxychlorophosphoranes,
P
the Wittig reaction,1 the Horner−Wadsworth−Emmons
reaction,2 and reactions promoted by Mitsunobu conditions.3
Such intermediates can undergo a fast intramolecular ligand
exchange process, termed Berry pseudorotation,4,5 that may
have a significant effect on the outcome of the reaction.6,7
However, in the case of the Appel reaction conditions,8 while
the involvement of chloro- and alkoxyphosphonium species is
well-established,9−11 the extent of participation of pentacoordi-
nate phosphorane intermediates is less clear.8,9
Our interest in this question arose through our develop-
ment12 of an asymmetric version of the Appel conditions
(Scheme 1) wherein racemic arylmethylphenylphosphines are
Scheme 2. Possible Sources of Stereoselection in the
Asymmetric Appel Process
a
Scheme 1. The Asymmetric Appel Process
a
HCA, hexachloroacetone; CPS, chlorophosphonium salt; DAPS,
diastereomeric alkoxyphosphonium salts; PCA, pentachloroacetonide.
treated with hexachloroacetone (HCA) and a chiral nonracemic
alcohol (R*OH) to give high yields of enantioenriched
phosphine oxides with enantiomeric excess (ee) up to 82%.
This reaction is an effective way to make certain P-stereogenic
phosphine oxides and bisphosphine oxides such as DiPAMPO
and analogues12,13 but is clearly limited by the moderate
selectivity. As part of our studies to raise the selectivity and
expand the substrate scope, we determined that the broad
course of the reaction is as shown in Scheme 1 for
Received: June 20, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo401318g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
which would be expected to undergo rapid interconversion via
Berry pseudorotation. Selection could then occur as a result of
the unequal distribution of pseudorotamers (dynamic thermo-
dynamic resolution) or by their unequal rates of collapse to
DAPS (dynamic kinetic resolution) or both. A rather different
possibility is shown as pathway B: reaction of the chiral alcohol
with rapidly interconverting CPS to generate directly the
unequal mixture of diastereomers (also a dynamic kinetic
resolution). The selectivity engendered by either pathway A or
B might also be either augmented or diminished by unequal
rates of the Arbusov collapse to oxides (pathway C) if the
DAPS species can interconvert. However, our preliminary
studies11 indicated that their ratios (as measured by 31P NMR
spectroscopy) remained relatively unchanged during the course
of the reaction and usually corresponded fairly consistently with
the ee’s in the product oxides.
and axial positions.4b The presence of the ring is also expected
to slow the Berry pseudorotation,4c,16b so if such pseudor-
otation is indeed involved in the stereoselection process, we
should expect a substantial change in ee relative to 2 under the
same conditions. We would also increase our chances of
detecting the pentacoordinate species by 31P NMR spectros-
copy, since the ring would also be expected to slow its
decomposition.7a,16b
Compounds such as 1 are a valuable synthetic challenge in
their own right (e.g., as ligands for catalytic asymmetric
hydrogenation17,18), but most syntheses of benzophospholanes
of type 1 have drawbacks.19 Herein we report the efficient
synthesis of the title compound, its subsequent use in the
asymmetric Appel process, the absolute configuration of the
resulting oxide, and the implications for the origin of the
stereoselectivity of the reaction.
Faced with these multiple possibilities, we sought ways to
simplify our analysis. We report here our studies focused on the
possible involvement of the pentacoordinate species (pathway
A) primarily by the synthesis of a compound designed to reveal
its influence.
Synthesis of the test compound. Our initial, fairly traditional,
synthesis of compound 1 (route A) is outlined in Scheme 3.
Reduction20 and bromination21 of 2-bromophenylacetic acid
(3) afforded dibromide 4 in 60% overall yield, which was then
subjected to the Arbusov reaction with triethyl phosphite to
give a good yield of phosphonate 5. A notable issue in the latter
reaction was the side reaction of ethyl bromide and triethyl
phosphite. Consumption of the dibromide required a very
substantial excess of triethyl phosphite, resulting in the
production of diethyl ethylphosphonate in significant excess
over the product 5 (ratio of 4:1), from which 5 had to be
purified by careful high-vacuum distillation. Intramolecular
cyclization of 5 with t-BuLi to give 1-ethoxy-2,3-dihydrophosp-
hole-1-oxide (6) proceeded in high yield, but the yield of the
subsequent conversion to 2,3-dihydro-1-phenylphosphole-1-
oxide (oxo-1) with phenylmagnesium bromide could not be
raised above 53%, despite extensive attempted optimization.
Ironically, this latter problem may be related to the reduced
reactivity of the five-membered cyclic pentacoordinated
phosphorus intermediate, the stratagem of this research in
the first place. Perhaps for similar reasons, the deoxygenation of
oxo-1 with trichlorosilane was also rather unsatisfactory, with
difficulties in the isolation of the product and, notably, the
persistent presence of oxo-1 following the reduction.
Rationale for the test compound. Previously we had seen no
evidence in the 31P NMR spectra of our reaction mixtures (in
toluene solvent) for the intervention of pentacoordinate
species, which might be expected in a region of moderately
low field shift (δP = −30 to −60 ppm)15 in this solvent, but we
were aware that this did not rule it out completely. Therefore,
we sought a system that should affect the rate of Berry
pseudorotation, in turn imparting a potential difference in
stereoselectivity. Inclusion of the phosphorus atom in a ring,
especially five-membered, is a well-known stratagem in
phosphorus chemistry that has been shown in many instances
to impact dramatically the kinetics and mechanism.7,16 We
chose 2,3-dihydro-1-phenylbenzo[b]phosphole (1-phenylphos-
phindane, 1), a cyclic analogue of methylphenyl(o-tolyl)-
phosphine (2) (Figure 1). The latter had been studied
Although we were able to access our target by route A, the
problems encountered prompted us to explore an alternative
ring-closing metathesis (RCM) route.22 In contrast to route A,
the phenyl group could be in place prior to the formation of the
benzophospholane. The RCM procedure we chose (route B) is
given in Scheme 4.
Starting from dichlorophenylphosphine, sequential addition
of the Grignard reagent derived from 2-bromostyrene at low
temperature followed by vinylmagnesium bromide resulted in
Figure 1. Comparison of phosphines 1 and 2.
extensively by us in the asymmetric Appel process and had
given the previous best enantioselectivity (up to 82% ee).12,14b
The linking of two of the ligands at phosphorus into a five-
membered ring introduces a limit on the number of possible
pseudorotamers because the ring can span easily only equatorial
Scheme 3. Synthesis of oxo-1 via Route A
B
dx.doi.org/10.1021/jo401318g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 4. Synthesis of oxo-1 via Route B Involving RCM Performed with Hoveyda−Grubbs Second-Generation Catalyst
the formation of phenylstyrylvinylphosphine (not isolated),
which was immediately oxidized in situ to the corresponding
oxide 7. The latter was unstable, decomposing upon attempted
purification, so the crude product was used directly in the next
step without purification. For the ring-closing metathesis, the
Hoveyda−Grubbs second-generation catalyst was found to be
optimal, resulting in the formation of 1-phenylbenzo[b]-
phosphole-1-oxide (8) with >90% conversion as judged by
31P NMR spectroscopy. Compounds of this type are also of
interest in their own right;23 notably, Matano and co-workers
recently used 8 in electronic studies of its dimer and related
compounds,24 but again, the syntheses are unsatisfactory. The
exocyclic double bond of phosphole oxide 8 was hydrogenated
with ease to give oxo-1 with an overall isolated yield of 80%
from dichlorophenylphosphine. For the final deoxygenation of
oxo-1, we were able to utilize a novel methodology recently
reported by our laboratory involving pretreatment with oxalyl
chloride (which generates a chlorophosphonium salt) followed
by reduction with lithium aluminum hydride.14,25 This
methodology was applied to the direct conversion of oxo-1
to phosphine 1 in a good yield of 80% isolated with only trace
amounts of oxide in the final material.
observed (δP = 89.3 and 89.5 ppm). However, at no point
during the reaction did we observe a signal for a
chloroalkoxyphosphorane. These results provide powerful
evidence against the involvement of pentacoordinate inter-
mediates and associated Berry pseudorotation in the stereo-
selectivity of the asymmetric Appel process.
Finally, it remained to check that the absolute configurations
of the product oxides were the same. We had previously
established that (R)-oxo-2 is the major enantiomer produced
with (−)-menthol.27 Crystallization of scalemic oxo-1 obtained
from the process proved unsuccessful, and we had to resort to
preparative CSP-HPLC of the racemic material. Crystals grown
of the major enantiomer were reconfirmed as such by analytical
CSP-HPLC, and one was analyzed by single-crystal X-ray
crystallography (details are provided in the Supporting
Information). The absolute configuration was indeed found
to be R, as expected if phosphines 1 and 2 are comparable
within the asymmetric Appel manifold.
In conclusion, we have developed two routes to the
phosphindane core structure. Route A provides the possibility
for variation of the pendant substituent at phosphorus by the
use of alternative nucleophiles with phosphonate 6. Route B is a
short, efficient synthetic route to both 1-phenylbenzo[b]-
phosphole oxide 8 and 1-phenyl-2,3,dihydrobenzo[b]-
phosphole 1, with scope for application toward the synthesis
of analogues with a central benzophospholane core. Likewise,
variation on the alkyl ring could be achieved by functionaliza-
tion of the double bond in oxide 8 or having functionality
preinstalled before the RCM step. Most importantly, the
availability of route B allowed us to study the stereoselection in
our asymmetric oxidation of tertiary phosphines, which
provided strong evidence against the involvement of Berry
pseudorotation in the selecting process.
Testing in the asymmetric Appel process. With the synthesis of
compound 1 established, we turned to probing the mechanism
of the asymmetric Appel process. Both 1 and 2 were treated
with HCA and chiral alcohol at a number of temperatures, and
the results are shown in Table 1. Our premise was that if Berry
Table 1. Results of the Asymmetric Appel Process as Applied
a
to Phosphines 1 and 2
b
ee (%)
c
c
entry
alcohol
T (°C)
oxo-1
oxo-2
1
2
3
4
(−)-menthol
(−)-menthol
(−)-menthol
(−)-8-phenylmenthol
0
−44
−80
−80
50
62
80
82
50
66
76
75
EXPERIMENTAL SECTION
■
General Experimental. All reagents were purchased from
commercial sources and unless noted otherwise were used as received
without further purification. All dry solvents were processed through a
Grubbs-type solvent purification system and stored over molecular
sieves (4 Å). All molecular sieves were flame-dried in a flask and
heated to ∼200 °C with a heat gun under vacuum prior to use. Flash
chromatography was performed on silica having a particle size of
0.04−0.06 mm. NMR spectra were recorded at 25 °C on 300−600
MHz spectrometers. Chemical shifts (δ) are reported in parts per
million relative to internal Me4Si. 13C NMR spectra were assigned with
the aid of two-dimensional cross-coupling experiments. All NMR
samples of air- or moisture-sensitive compounds were made up under
nitrogen in dry CDCl3 in a Schlenk tube designed specifically for NMR
preparation that could be dried and backfilled via standard Schlenk
techniques. CDCl3 was dried over activated molecular sieves (4 Å)
under an atmosphere of nitrogen and stored in a Schlenk flask over
sieves. High-resolution mass spectrometry was carried out on a
electrospray ionization mass spectrometer with a TOF analyzer. IR
spectra were obtained on an FTIR spectrometer and are reported here
in units of cm−1. Samples were prepared as thin films between NaCl
plates. Phenyl(methyl)(o-tolyl)phosphine and its corresponding oxide
were synthesized as per previous reports by our group.10
a
Conditions: HCA (0.11 M), phosphine (0.11 M), alcohol (0.132 M);
for the detailed procedure, see the Experimental Section. Yields were
>95%, and no other products were visible in the 31P NMR spectra.
b
c
Measured by CSP-HPLC. The configuration of oxo-1 was
determined to be R (see the text); the configuration of oxo-2 was
previously determined to be R.27
pseudorotation is involved in the stereoselection, then a
significantly different selectivity should result upon introduction
of the ring. However, the results obtained26 with (−)-menthol
(entries 1−3) showed that across a wide temperature range, the
selectivity obtained with phosphine 1 tracked well with that for
phosphine 2. For completeness, we also checked selectivity
with a different alcohol, choosing (−)-8-phenylmenthol as it
had previously shown a slightly different selectivity profile
compared with (−)-menthol.12 Again, there was no significant
difference (entry 4). The reaction of 1 was also followed by 31
P
NMR spectroscopy, and signals corresponding to DAPS were
C
dx.doi.org/10.1021/jo401318g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2-(2-Bromophen-1-yl)ethanol.20 To a solution of 2-bromophe-
nylacetic acid (10 g, 46.5 mmol, 1 equiv) in dry THF (20 mL) cooled
in an ice water bath were added NaBH4 pellets (2.28 g, 60.4 mmol, 5.2
eq. of hydride) under a flow of nitrogen in lots over 15 min. To the
resulting mixture was added BF3·Et2O (8.6 mL, 70 mmol, 1.5 equiv)
dropwise by syringe over 15 min. A white precipitate was noted. The
mixture was allowed to stir at room temperature for 24 h and was
Ar), 132.6 (d, 4JPC = 2.5 Hz, Ar), 130.3 (d, 1JPC = 130.8 Hz, Ar), 127.6
3
3
(d, JPC = 9.0 Hz, Ar), 127.3 (d, JPC = 10.8 Hz, Ar), 126.9 (d, JPC
=
12.9 Hz, Ar), 61.1 (d, 2JPC = 6.5 Hz, O−CH2), 26.0 (d, 3JPC = 6.5 Hz,
3
Ar−CH2), 23.7 (d, 1JPC = 96.5 Hz), 16.5 (d, JPC = 6.1 Hz, CH3). 31P
NMR (121 MHz, CDCl3): δ 65.3. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C10H13O2PH 197.0731, found 197.0727. IR: 2983, 2936,
1598, 1211 (PO) cm−1.
1
monitored by H NMR spectroscopy by sampling the mixture and
1-Phenyl-2,3-dihydrobenzo[b]phosphole-1-oxide (oxo-1) by
Route A. A dry nitrogen-flushed flask was charged with a solution of 6
(0.75 g, 3.82 mmol 1 equiv) in dry THF (50 mL) and cooled in an
ice−water bath. Phenylmagnesium chloride (2.0 M in THF, 2.66 mL,
5.34 mmol, 2.5 equiv) was added dropwise via syringe over 30 min,
and the mixture was stirred for 15 min at 0 °C. This mixture was
slowly heated to reflux for 6 h, and a dark-brown color was noted. The
mixture was cooled to −10 °C, and the THF was removed under
reduced pressure. To this was added ethyl acetate (100 mL), and the
mixture was quenched with aq. HCl (1.0 M) at −10 °C until a neutral
pH was obtained. The combined organic phases were dried over
MgSO4 and concentrated under reduced pressure to yield a dark oil.
This was purified by flash chromatography on silica (70:30 ethyl
acetate/cyclohexane) to yield the desired product as a pale-yellow
solid. Subsequent recrystallization from hot ethyl acetate and
cyclohexane afforded pale-yellow crystals (0.35 g, 53.5%, mp 73−77
°C). See below for characterization.
carrying out a workup as below. Upon completion, the THF was
removed under reduced pressure, and the mixture was quenched by
addition of HCl (100 mL, 1 M). To this was added ethyl acetate (50
mL), and the mixture was washed with sat. NaHCO3 (50 mL × 2)
followed by a final wash with brine (50 mL × 2). The organic layer
was further dried over Na2SO4 and concentrated under reduced
pressure to yield a pale-yellow oil (7.40 g, 70%). 1H NMR (300 MHz,
CDCl3): δ 7.54−7.52 (m, 1H, ArH), 7.29−7.19 (m, 2H, ArH), 7.10−
7.03 (m, 1H, ArH) 3.84 (t, J = 7.5 Hz, 2H, HO−CH2) 3.00 (t, J = 7.5
Hz, 2H, Ar−CH2). In accordance with the literature, used without
further purification.
2-(2-Bromophen-1-yl)ethyl Bromide (4).21 The oil from the
previous procedure was added to a nitrogen-flushed two-neck round-
bottom flask equipped with a condenser. To this neat PBr3 (3.8 mL, 40
mmol, 1.2 equiv) was added slowly via syringe dropwise over 30 min
at room temperature. The mixture was heated to 80 °C and stirred at
this temperature for 2 h. The solution was then cooled to 0 °C, diluted
with DCM (100 mL), quenched with sat. NaHCO3 (2 × 50 mL), and
finally washed with distilled H2O (2 × 50 mL). The organic layer was
dried over Na2SO4 and concentrated under reduced pressure to an oil.
This was purified using flash chromatography on silica (80:20
cyclohexane/ethyl acetate) to afford a clear oil (7.57 g, 85%). 1H
NMR (300 MHz, CDCl3): δ 7.5 (d, J = 8.4 Hz, 1H, ArH), 7.27−7.24
(m, 2H, ArH), 7.14−7.08 (m, 1H, ArH), 3.58 (t, J = 7.5 Hz, 2H, Br−
CH2), 3.28 (t, J = 7.6 Hz, 2H, Ar−CH2). In accordance with the
literature, used without further purification.
1-Phenyl-2,3,dihydrobenzo[b]phosphole (1) via Silane Re-
duction. To a solution of oxo-1 (0.5 g, 2.14 mmol) in toluene (10
mL) was added trichlorosilane (3.0 mL, 21.4 mmol). The reaction
mixture was stirred at room temperature for 3.5 h. After hydrolysis
with excess 30% NaOH (10 mL), the organic layer was separated, and
the aqueous layer was extracted with diethyl ether (2 × 25 mL). The
combined extracts were washed with water (2 × 10 mL), dried over
Na2SO4, filtered, and concentrated, yielding 1 (0.35 g, 76%) as a pale-
yellow oil. See below for characterization.
Phenyl(o-vinylphenyl)(vinyl)phosphine Oxide (7). To a dry
nitrogen-flushed two-neck flask charged with magnesium turnings
(0.28 g, 11.5 mmol, 1 equiv), 1 mL of a solution of 2-bromostyrene
(2.6 g, 14 mmol, 1.2 equiv) in dry THF (5 mL) was added dropwise
via syringe at room temperature, and initiation was noted. The
remaining 2-bromostyrene solution (4 mL) was added dropwise via
syringe over 10 min, followed by dry THF (10 mL). The mixture was
heated to reflux and stirred for 3 h until the magnesium was
consumed. In a dry nitrogen-flushed two-neck flask, a solution of
dichlorophenylphosphine (2.1 g, 11.5 mmol, 1 equiv) in dry THF
(100 mL) was prepared. This was cooled to −78 °C using a dry ice−
acetone bath. To this the above prepared Grignard solution was added
dropwise via syringe over 20 min, and a yellow color was noted upon
addition. The mixture was allowed to warm to room temperature.
Formation of solely the monoaddition product was confirmed by 31P
NMR analysis following removal of a sample via syringe and workup
by filtration after dissolution in CDCl3. Following this, the solution
was cooled using in an ice−water bath, and vinylmagnesium bromide
solution (14 mL, 14 mmol, 1 M, 1.2 equiv) in THF was added via a
dropping funnel over 20 min. The resulting mixture was allowed to
warm to room temperature and stirred overnight. The mixture was
concentrated under reduced pressure to a slurry. To this degassed
DCM (100 mL) was added, and the reaction was quenched using
degassed sat. NH4Cl solution (100 mL). The mixture was
concentrated to give a yellow oil. Acetonitrile (50 mL) was added,
and the mixture was cooled in an ice−water bath. To the mixture was
added H2O2 (3 equiv, 30% w/v) dropwise via syringe over 10 min, and
the solution was stirred for 1 h. To this was added H2O (20 mL), and
acetonitrile was removed under reduced pressure, leaving a cloudy
aqueous solution. Caution: do not evaporate to dryness. This was
extracted with DCM (100 mL), and the combined organic layer was
dried over MgSO4 and concentrated under reduced pressure to yield a
yellow solid (crude yield 2.38 g, >90%). 1H NMR (CDCl3, 600 MHz):
δ 7.67−7.62 (m, 4H, ArH), 7.54−7.49 (m, 2H, ArH), 7.47−7.42 (m,
Diethyl 2-(2-Bromophen-1-yl)ethylphosphonate (5). In a dry
nitrogen-flushed flask, a neat mixture of 4 (5.6 g, 21.3 mmol, 1 equiv)
and triethyl phosphite (16 mL, 96 mmol, 4.5 equiv) was stirred at 135
°C. When the reaction was complete (6 h, as determined by 31P
NMR), the side product, diethyl ethylphosphite, was removed by high-
vacuum distillation, leaving behind the required product as a colorless
liquid (6.48 g, 94%). 1H NMR (300 MHz, CDCl3): δ 7.53 (d, J = 7.6
Hz, 1H, ArH), 7.24−7.26 (m, 2H, ArH), 7.06−7.11 (m, 1H, ArH),
4.06−4.16 (m, 4H, O−CH2), 2.98−3.07 (m, 2H, P−CH2), 2.03−2.13
(m, 2H, Ar−CH2), 1.33 (t, J = 7.1 Hz, 6H, CH3). 13C NMR (101
MHz, CDCl3): δ 140.2, 132.9, 130.2, 128.1, 127.6, 124.0, 61.6 (d, 2JPC
2
1
= 6.5 Hz, O−CH2), 29.4 (d, JPC = 3.9 Hz, Ar−CH2), 25.8 (d, JPC
=
3
139.3 Hz, P−CH2), 16.4 (d, JPC = 6.1 Hz, CH3). 31P NMR (121
MHz, CDCl3): δ 30. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C12H19BrO3PH 321.0255, found 321.0267. IR: 3054, 2985, 1265 (P
O) cm−1. Used without further purification.
1-Ethoxy-2,3-dihydrobenzo[b]phosphole-1-oxide (6). To a
dry nitrogen-flushed flask was added a solution of 5 (3.0 g, 9.3 mmol, 1
equiv) in dry THF (30 mL), and the flask was cooled under nitrogen
in a dry ice−acetone bath. t-BuLi (1.7 M in pentane, 11.0 mL, 18.7
mmol, 2.1 equiv) was added dropwise via syringe over 30 min. After
the mixture was stirred for 1 h at −78 °C, the solution was allowed to
warm to room temperature, where the mixture turned pale-yellow and
was stirred for a further 30 min. The mixture was then cooled to −50
°C, quenched by the addition of water (25 mL) dropwise via syringe,
and diluted subsequently with ethyl acetate (100 mL). This mixture
was allowed to warm to room temperature, and the separated organic
layer was washed with brine (25 mL), dried over MgSO4, and
concentrated under reduced pressure to yield a pale-yellow oil. The
crude product was purified by flash chromatography on silica (90:10
cyclohexane/ethyl acetate) to yield the desired product as a colorless
oil (1.63 g, 90.5% yield). 1H NMR (400 MHz, CDCl3): δ 7.72
(apparent t, J = 8.4 Hz, 1H, ArHperi), 7.44−7.53 (m, 1H, ArH), 7.28−
7.38 (m, 2H, ArH), 4.00−4.26 (dq, J = 7 Hz, 2H, O−CH2), 3.04−3.19
(m, 2H, P−CH2), 2.08−2.24 (m, 2H, Ar−CH2), 1.32 (t, J = 7.0 Hz,
3H, CH3). 13C NMR (101 MHz, CDCl3): δ 146.2 (d, JPC = 37.5 Hz,
2H, ArH), 7.36−7.32 (m, 1H, ArH), 7.24 (dd, Jtrans = 17.2 Hz, Jcis
=
10.9 Hz, 1H, Ar−CH), 6.71 (m, 1H, P−CH), 6.37−6.25 (m, 2H, P−
CH−CH2), 5.60 (dd, Jtrans = 17.2 Hz, Jgem = 1 Hz, 1H, Ar−CH−CHa),
D
dx.doi.org/10.1021/jo401318g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
5.20 (dd, Jcis = 10.9 Hz, Jgem = 1 Hz, 1H, Ar−CH−CHb). 13C NMR
removed under reduced pressure, and the mixture was quenched by
addition of 20 mL of degassed ethyl acetate followed by slow addition
of aq. HCl (1M) via syringe over 5 min. The aqueous layer was further
extracted with degassed ethyl acetate (20 mL), and the combined
organic layers were dried over MgSO4, passed through a short silica
plug, and concentrated under reduced pressure to yield a yellow oil
(151 MHz, CDCl3): δ 142.2 (d, 2JPC = 7.5 Hz, ArCortho), 135.3 (d, 3JPC
1
= 5.8 Hz, Ar−CH−CH2), 134.8 (P−CH−CH2), 133.1 (d, JPC = 103
2
Hz, PhCipso) 132.9 (d, JPC = 11.5 Hz, PhCpara), 131.9 (d, JPC = 3 Hz,
3
ArCHortho), 132.4 (d, JPC = 3 Hz, ArCHmeta), 131.3 (PhCmeta), 131.5
(d, 1JPC = 99 Hz, P−CH−CH2), 129.5 (d, 1JPC = 99 Hz, ArCipso) 128.6
(d, 2JPC = 12.2 Hz, PhCortho), 127.3 (d, 4JPC = 12.3 Hz, ArCHpara), 127
(0.45 g, 80%). 1H NMR (500 MHz, CDCl3): δ 7.65 (apparent t, JHH
=
3
(d, JPC = 10.1 Hz, ArCHmeta), 117.2 (Ar−CH−CH2). 31P NMR
8.5 Hz, 1H, Ar−Hperi) 7.61−7.35 (m, 8H, Ar), 3.22−3.07 (m, 2H, Ar−
CH2), 2.36−2.26 (m, 1H, P−CH), 2.02−2.12 (m, 1H, P−CH). 13C
(CDCl3 121 MHz): δ 25.0. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C16H15OPNa 277.0753, found 277.0761. IR: 3081, 3058, 1656,
1261 (PO) cm−1. Used in the next step without further purification.
1-Phenylbenzo[b]phosphole-1-oxide (8). To a dry flask
charged with nitrogen was added the solid from the previous
procedure (2.38 g, 10 mmol, 1 equiv) followed by dry toluene (150
mL). This was heated to 60 °C, and Hoveyda−Grubbs second-
generation catalyst (0.15 g, 2.5 mol %) was added as a solid. The
mixture was stirred at 60 °C under nitrogen and monitored by 31P
NMR by removal of 1 mL portions, which were filtered through a pad
of Celite and concentrated. Once the starting material had been
consumed after 24 h, the mixture was concentrated under reduced
pressure to yield a green solid (>90%, 2.85 g). 1H NMR (CDCl3, 500
MHz): δ 7.73−7.69 (m, 2H, ArH), 7.62−7.59 (m, 1H, ArH), 7.34−
7.53 (m, 6H, ArH; 1H, Ar−CH), 6.45 (dd, 2JPH = 25 Hz, JHH2 = 8 Hz,
1H, P−CH). 13C NMR (126 MHz, CDCl3): δ 145.34 (d, JPC = 13
2
NMR (101 MHz, CDCl3): δ 149.5 (d, JPC = 3 Hz, ArC2ortho), 139.9
(d, 1JPC = 44 Hz, ArCipso), 139.8 (d, 1JPC = 60 Hz, PhCipso), 131.48 (d,
2JPC = 17 Hz, PhCortho), 131.46 (d, JPC = 25 Hz, ArCHperi), 129.1 (s,
2
ArC4meta), 128.3 (d, 4JPC = 6.3 Hz, PhCpara), 128.1 (s, PhCmeta), 126.8
(d, 4JPC = 8.3 Hz, ArCpara), 125 (d, 3JPC = 3 Hz, ArC2meta), 27.7 (d, 1JPC
= 9 Hz, P-CH2), 34.4 (d, 3JPC = 6 Hz, Ar-CH2). 31P NMR (121 MHz,
CDCl3): δ −2.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H13PH 213.0833, found 213.0825.
Preparation of Stock Solutions. Molecular sieves (∼25, 4 Å)
were added to a dry 100 mL nitrogen-flushed flask, flame-dried, and
placed under reduced pressure and left to cool. Following this, the
flask was heated for 2 min, concentrating on the sieves, and then
allowed to cool before being backfilled with nitrogen three times via
standard Schlenk techniques. In a separate flask under a flow of
nitrogen, the reagent (menthol or HCA or phosphine) and dry
toluene were added to prepare the desired solution. This was then
transferred via cannula under a flow of nitrogen directly into flask
containing the sieves and left for 24 h prior to use.
Procedure for Asymmetric Appel Reaction. A 50 mL Schlenk
flask equipped with molecular sieves (∼1 g, 4 Å) and a magnetic stirrer
was flame-dried and placed under reduced pressure and left to cool.
Following this, the flask was heated for 2 min, concentrating on the
sieves, and then allowed to cool before being backfilled with nitrogen
three times via standard Schlenk techniques. Dry toluene (3 mL), a
solution of menthol in dry toluene (3 mL, 0.396 mmol, 0.132 M, 1.2
equiv), and a solution of HCA in dry toluene (3 mL, 0.330 mmol, 0.11
M, 1 equiv) were added and left over sieves for 1 h. The mixture was
cooled to the desired temperature (dry ice−acetone, dry ice−
acetonitrile, or ice−water bath). Following this, a solution of
phosphine in dry toluene (3 mL, 0.330 mmol, 0.11 M, 1 equiv) was
added dropwise over 10 min. The temperature was maintained, and
the mixture was allowed to stir for 1 h. Following this, the mixture was
allowed to warm to room temperature overnight and then heated to 50
°C and stirred for 2 h. On cooling, the mixture was filtered and
concentrated under reduced pressure to give an oil, which was
dissolved in HPLC eluent to give a homogeneous solution. The
solution was filtered through an PTFE membrane (0.2 μm) syringe
filter directly into a vial, and analysis was carried out by HPLC.
HPLC Conditions. 1-Phenyl-2,3-dihydrobenzo[b]phosphole-1-
oxide (oxo-1). CHIRALPAC IA column, 90:10 heptane/ethanol,
flow rate 1 mL/min. Retention times: 20.5 min for (R)-oxo-1 and 22.2
min for (S)-oxo-1.
1
1
Hz), 141 (d, JPC = 30 Hz), 132 (d, JPC = 2.0), 131.3 (d, JPC = 3),
129.7, 129.8, 128.6 (d, JPC = 10.4), 127.9 (d JPC = 10 Hz) 127.8,
128.94, 126.8 (d, JPC = 99 Hz, P−CH), 124.9 (d, JPC = 13 Hz). 31P
NMR (CDCl3, 121 MHz): δ 41.2. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C14H11OPH 227.0626, found 227.0622. IR: 3056, 2963,
1630, 1262 (PO) cm−1. Used in the next step without further
purification.
1
3
1-Phenyl-2,3-dihydrobenzo[b]phosphole-1-oxide (oxo-1) by
Route B. The green solid from the previous procedure (2.20 g, 11
mmol, 1 equiv) was added to a round-bottom flask, followed by
MeOH (150 mL). To this was added 5 mol % Pd/C (10% w/w). The
flask was degassed by brief application of a vacuum and then was
charged with hydrogen via a balloon, and the mixture was stirred
vigorously for 48 h. The reaction mixture was filtered through a pad of
Celite and concentrated under reduced pressure to give a dark solid
(2.3 g, quantitative). To this was added DCM (100 mL), and the
solution was washed with 2 N nitric acid (50 mL). The organic layer
was dried over MgSO4 and concentrated under reduced pressure to
yield a pale-brown oil (1.9 g). Recrystallization from hot cyclohexane
and acetone afforded pale-brown crystals. 1H NMR (400 MHz,
CDCl3): δ 7.61−7.67 (m, 9H, ArH), 3.36−3.50 (m, 1H, CHb), 3.12−
3.25 (m, 1H, P−CHa), 2.33−2.53 (m, 2H, Ar−CH2). 13C NMR (101
MHz, CDCl3): δ 147.7 (d, JPC = 31 Hz, ArCortho), 132.9 (d, 1JPC = 98
Hz, ArCipso), 132.9 (d, 3JPC = 3 Hz, ArCpara), 132.4 (d, 1JPC = 103 Hz,
3
3
PhCipso), 131.8 (d, JPC = 3 Hz, Armeta), 130.7 (d, JPC = 10.4 Hz,
2
2
Armeta), 129.2 (d, JPC = 9.5 Hz, ArCperi), 128.7 (d, JPC = 12 Hz,
Phortho), 128 (d, JPC = 10 Hz, Phpara), 126.6 (d, JPC = 11.3 Hz,
PhCmeta), 28.4 (d, JPC = 4 Hz, Ar−CH2), 28.2 (d, JPC = 70 Hz, P−
CH2). 31P NMR (162 MHz, CDCl3): δ 53.2. HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C14H13OPH 229.0782, found 229.0779.
3
3
2
1
Phenyl(methyl)(o-tolyl)phosphine oxide (oxo-2). CHIRALPAC
IA column, 80:10 heptane/ethanol, flow rate 1 mL/min. Retention
times: 8.9 min for (S)-oxo-2 and 9.8 min for (R)-oxo-2.
1-Phenyl-2,3,dihydrobenzo[b]phosphole (1) via Oxalyl
Chloride/Hydride Reduction. In a dry nitrogen-flushed flask, a
solution of oxo-1 (0.60 g, 2.6 mmol, 1 equiv) in dry DCM (10 mL)
was prepared under nitrogen and cooled in an ice−water bath, and
oxalyl chloride (0.27 mL, 3.2 mmol, 1.25 equiv) was added dropwise
via syringe over 5 min. Bubbling was noted, and the mixture turned a
light orange and was allowed to warm to room temperature. A sample
was taken via syringe and added to a dry nitrogen-flushed flask; the
solvent was removed under reduced pressure, and the resulting solid
was dissolved in dry CDCl3. The sample was prepared under nitrogen
for NMR analysis, and the complete formation of the chlorophos-
phonium salt was confirmed by 31P NMR (δ 89.8). The mixture was
cooled in an ice−water bath, and to this LiAlH4 (1.3 mL, 4 M in
diethyl ether, 4 hydride equiv) was added dropwise via syringe over 15
min. A suspension was noted. Following this, the mixture was allowed
to warm to room temperature and stirred for 2 h. The solvent was
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, and 31P NMR spectra; HPLC analysis for the Appel
reaction procedure; and crystallographic data (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: declan.gilheany@ucd.ie.
Notes
The authors declare no competing financial interest.
E
dx.doi.org/10.1021/jo401318g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(17) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518−8519.
ACKNOWLEDGMENTS
■
(18) Liu, D.; Gao, W.; Wang, C.; Zhang, X. Angew. Chem., Int. Ed.
2005, 44, 1687−1689.
This research was supported by Science Foundation Ireland
(Grant 09/IN.1/B2627). We are also very grateful to the UCD
Centre for Synthesis and Chemical Biology (CSCB) and the
UCD School of Chemistry and Chemical Biology for access to
their extensive analysis facilities.
(19) From 1-phenyl-cis-3a,7a-dihydrophosphindole: (a) Quin, L. D.;
Rao, N. S.; Topping, R. J.; McPhail, A. T. J. Am. Chem. Soc. 1986, 108,
4519−4526. (b) Quin, L. D.; Rao, N. S. J. Org. Chem. 1983, 48, 3754−
3759. From the analogous menthyl phosphonate with multiple
recrystallization: (c) Imamoto, T.; Yoshizawa, T.; Hirose, K.; Wada, Y.;
Masuda, H.; Yamaguchi, K.; Seki, H. Heteroat. Chem. 1995, 6, 99−104.
Via intramolecular asymmetric phosphination: (d) Brunker, T. J.;
Anderson, B. J.; Blank, N. F.; Glueck, D. S.; Rheingold, A. L. Org. Lett.
2007, 9, 1109−1112. Via radical intramolecular benzannulation:
REFERENCES
■
(1) (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863−927.
(b) Byrne, P. A.; Gilheany, D. G. Chem. Soc. Rev. 2013, 42, 6670−
6696. (c) Vedejs, E.; Peterson, M. J. Top. Stereochem. 2007, 21, 1−157.
(2) Walker, B. J. Transformations via Phosphorus-Stabilized Anions
2: PO-Activated Olefination. In Organophosphorus Reagents in Organic
Synthesis; Cadogan, J. I. G., Ed.; Academic Press: London, 1979;
Chapter 3, pp 155−197.
(3) (a) Varasi, M.; Walker, K. A. M.; Maddox, M. L. J. Org. Chem.
1987, 52, 4235−4238. (b) Swamy, K. C. K.; Kumar, N. N. B.;
Balaraman, E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551−2651.
(4) (a) Berry, R. S. J. Chem. Phys. 1960, 32, 933−938. (b) Holmes, R.
R. In Pentacoordinated Phosphorus, Vol. 1: Structure and Spectroscopy;
ACS Monograph Series, Vol. 175; American Chemical Society:
Washington, DC, 1980. (c) Holmes, R. R. In Pentacoordinated
Phosphorus, Vol. 2: Reaction Mechanisms; ACS Monograph Series, Vol.
176; American Chemical Society: Washington, DC, 1980.
̌
(e) Mohar, B.; Cusak, A.; Modec, B.; Stephan, M. J. Org. Chem. 2013,
78, 4665−4673.
(20) Pasternak, A.; Shahripour, A.; Tang, H.; Teumelsan, N. H.;
Yang, L.; Zhu, Y.; Walsh, S. P. Int. Patent WO 2010129379 A1, 2010.
(21) Chuang, T.-H.; Fang, J.-M.; Jiaang, W.-T.; Tsai, Y.-M. J. Org.
Chem. 1996, 61, 1794−1805.
(22) (a) For RCM with phosphorus compounds, see: Harvey, J. S.;
Malcolmson, S. J.; Dunne, K. S.; Meek, S. J.; Thompson, A. L.;
Schrock, R. R.; Hoveyda, A. H.; Gouverneur, V. Angew. Chem., Int. Ed.
2009, 48, 762−766. (b) For RCM in the corresponding indole, see:
Bennasar, M. L.; Roca, T.; Monerris, M.; García-Díaz, D. J. Org. Chem.
2006, 71, 7028−7034. (c) For RCM to phospholane boranes, see:
Wu, X.; O’Brien, P.; Ellwood, S.; Secci, F.; Kelly, B. Org. Lett. 2013, 15,
192−195.
(5) Couzijn, E. P. A.; Slootweg, J. C.; Ehlers, A. W.; Lammertsma, K.
J. Am. Chem. Soc. 2010, 132, 18127−18140.
(23) (a) Decken, A.; Bottomley, F.; Wilkins, B. E.; Gill, E. D.
Organometallics 2004, 23, 3683−3693. (b) Hayato, T.; Kosuke, S.;
Laurean, I.; Yoshimitsu, I.; Yoshiharu, S.; Eiichi, N. Org. Lett. 2008, 10,
2263−2265. (c) Takanobu, S.; Kentaro, S.; Taigo, K.; Masato, T. Org.
Lett. 2008, 10, 2689−2692 and references cited therein.
(24) Hayashi, Y.; Matano, Y.; Suda, K.; Kimura, Y.; Nakao, Y.;
Imahori, H. Chem.Eur. J. 2012, 18, 15972−15983.
(6) García Lop
García-Granda, S.; Iglesias, M. J.; Ona-Burgos, P.; Lop
́
ez, J.; Moran
́
Ramallal, A.; Gonzal
́
ez, J.; Roces, L.;
ez Ortiz, F. J.
́
̃
Am. Chem. Soc. 2012, 134, 19504−19507.
(7) (a) Vedejs, E.; Marth, C. F. J. Am. Chem. Soc. 1989, 111, 1519−
1520. (b) Vedejs, E.; Marth, C. F. J. Am. Chem. Soc. 1990, 112, 3905−
3909.
(25) Byrne, P. A.; Rajendran, K. V.; Muldoon, J.; Gilheany, D. G. Org.
Biomol. Chem. 2012, 10, 3531−3537.
(8) (a) Downie, I. M.; Holmes, J. B.; Lee, J. B. Chem. Ind. (London)
1966, 900−901. (b) Appel, R.; Halstenberg, M. Tertiary Phosphane
Halogenoalkane Reagents. In Organophosphorus Reagents in Organic
Synthesis; Cadogan, J. I. G., Ed.; Academic Press: London, 1979;
Chapter 9, pp 387−432.
(9) (a) Weiss, R. G.; Snyder, E. I. J. Org. Chem. 1971, 36, 403−406.
(b) Jones, L. A.; Sumner, C. E., Jr.; Franzus, B.; Huang, T. T. S.;
Snyder, E. I. J. Org. Chem. 1978, 43, 2821−2827. (c) Dabbagh, H. A.;
Franzus, B.; Huang, T. T. S.; Davis, B. H. Tetrahedron 1991, 47, 949−
960.
(10) (a) Denton, R. M.; An, J.; Adeniran, B. Chem. Commun. 2010,
46, 3025−3027. (b) Denton, R. M.; An, J.; Adeniran, B.; Blake, A. J.;
Lewis, W.; Poulton, A. M. J. Org. Chem. 2011, 76, 6749−6767.
(11) Rajendran, K. V.; Gilheany, D. G. Chem. Commun. 2012, 48,
10040−10042.
(26) Molecular sieves in the reaction mixture are necessary to keep it
dry during the reaction. As discussed previously (ref 12a), water has a
strong detrimental effect by hydrolysis of reactive intermediates, which
results in racemic phosphine oxide formation. For the cyclic case
reported here (1), a control was also carried out with no molecular
sieves, which showed a detrimental effect on the ee, lowering it by 16%
(the HPLC trace is included in the Supporting Information). This
reduction is consistent with that obtained previously (ref 12a) for the
acyclic system (2).
(27) King, G.; Bergin, E.; Mueller-Bunz, H.; Gilheany, D. G. Acta.
Crystallogr., Sect. E 2007, 63, O3278.
(12) (a) Bergin, E.; O’Connor, C. T.; Robinson, S. B.; McGarrigle, E.
M.; O’Mahony, C. P.; Gilheany, D. G. J. Am. Chem. Soc. 2007, 129,
9566−9567. (b) Rajendran, K. V.; Kennedy, L.; Gilheany, D. G. Eur. J.
Org. Chem. 2010, 5642−5649.
(13) Gilheany, D. G.; Robinson, S. B.; O’Mahony, C. P.; O’Connor,
C. T.; Bergin, E.; Walsh, D. M.; Clarke, E. F.; Kelly, B. G.; McGarrigle,
E. M. Int. Patent WO 118603, 2005.
(14) (a) Rajendran, K. V.; Gilheany, D. G. Chem. Commun. 2012, 48,
817−819. (b) Rajendran, K. V.; Kudavalli, J. S.; Dunne, K. S.;
Gilheany, D. G. Eur. J. Org. Chem. 2012, 2720−2723.
(15) (a) Dichlorotriphenylphosphorane has been reported at −47
ppm in benzene-d6. See: Godfrey, S. M.; McAuliffe, C. A.; Pritchard, R.
G.; Sheffield, J. M. Chem. Commun. 1998, 921−922. (b)
Diethoxytriphenylphosphorane has been reported at −55 ppm in
benzene-d6. See: Mathieu-Pelta, I.; Evans, S. A. J. Org. Chem. 1994, 59,
2234−2237. Alkyl substitution should lead to a downfield shift.
(16) (a) Westheimer, F. H. Acc. Chem. Res. 1968, 1, 70−78.
(b) O’Brien, C. J.; Tellez, J. L.; Nixon, Z. S.; Kang, L. J.; Carter, A. L.;
Kunkel, S. R.; Przeworski, K. C.; Chass, G. C. Angew. Chem., Int. Ed.
2009, 48, 6836−6839. (c) Byrne, P. A.; Gilheany, D. G. J. Am. Chem.
Soc. 2012, 134, 9225−9239.
F
dx.doi.org/10.1021/jo401318g | J. Org. Chem. XXXX, XXX, XXX−XXX