Desymmetrization Approach to the Synthesis of Optically Active P-Stereogenic Phosphin-2-en-4-ones

Article abstract of DOI:10.1021/acs.joc.0c03055

Two synthetic protocols for the conversion of 1-phenylphosphinan-4-ones to novel P-stereogenic 1-phenylphosphin-2-en-4-ones by enantioselective deprotonation followed by oxidation and by asymmetric organocatalytic halogenation accompanied by elimination have been developed. These two-step one-pot transformations provide convenient access to optically active 1-phenylphosphin-2-en-4-one 1-sulfide and 1-phenylphosphin-2-en-4-one 1-oxide of 96 and 55% enantiomeric purities, respectively.

Full text of DOI:10.1021/acs.joc.0c03055

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Desymmetrization Approach to the Synthesis of Optically Active
P‑Stereogenic Phosphin-2-en-4-ones
̇
Elzbieta Łastawiecka, Sławomir Frynas, and K. Michał Pietrusiewicz*
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ABSTRACT: Two synthetic protocols for the conversion of 1-
phenylphosphinan-4-ones to novel P-stereogenic 1-phenylphos-
phin-2-en-4-ones by enantioselective deprotonation followed by
oxidation and by asymmetric organocatalytic halogenation
accompanied by elimination have been developed. These two-
step one-pot transformations provide convenient access to
optically active 1-phenylphosphin-2-en-4-one 1-sulfide and 1-
phenylphosphin-2-en-4-one 1-oxide of 96 and 55% enantiomeric
purities, respectively.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Of the known synthetic methods used frequently for
desymmetrization of prochiral ketones,10 enantioselective
deprotonation,10a10b and enantioselective α-halogenation,10f10g
seemed to be most suitable for accomplishing our goal.
Accordingly, the two alternative paths that we have designed
to lead to optically active 4 are based on these two
desymmetrization processes (Scheme 1).
The desymmetrization by path A involves asymmetric
deprotonation of 1-phenylphosphinan-4-one (1) by a chiral
base and conversion of the resulting lithium enolate to the silyl
enol ether 2 by quenching with TMSCl.10a10b The desymmet-
rization by path B entails transformation of phosphinanone 1
into a chiral α-halogenated derivative 3, which could be achieved
by organocatalytic asymmetric α-halogenation.10f10g Both
synthetic procedures make use of the ketone functionality of
phosphinanone 1, and both result in the overall asymmetric
transformation of the remote prochiral phosphorus center in
ketone 1 into a P-stereogenic one in enone 4 via intermediate 2
or 3.
Cyclic nonracemic phosphines constitute an important group of
organophosphorus compounds that are sought for their
advantageous performance as organocatalysts and as ligands in
various asymmetric processes.1 Numerous chiral five-membered
(phospholane)2 and four-membered (phosphetane) ligands3
have been developed to meet the demand. In contrast, the
corresponding chiral six-membered carbon-phosphorus hetero-
cycles (phosphinanes) have received relatively little attention4,5
due, most probably, to scarcity of convenient methods enabling
their synthesis in suitably functionalized and nonracemic forms.6
For illustration, all the optically active phosphines and
phosphine oxides containing phosphorus embedded in the six-
membered ring, which have been synthesized to date, are
collected in Figure 1A,B.
There has recently been considerable interest in preparation
of P-stereogenic phosphorus compounds by desymmetrization
reactions starting from P-prochiral precursors.7 Synthesis of
cyclic phosphine derivatives by this route can start either from an
acyclic,4e4i or from a cyclic8,9 precursor. In the latter case, the
reported precedents included phosphol-3-ene oxide8 and its
epoxide,9 phosphetane sulfide,3d and phospholane sulfide2f as
well as phospholane borane and phosphinane boranes.4a In this
paper, we wish to report our results on evaluation of
enantioselective desymmetrization of 1-phenylphosphinan-4-
one (1) by employing its carbonyl function in two independent
two-step processes designed to lead to the formation of optically
active 1-phenylphosphin-2-en-4-one derivatives 4 (Figure 1C).
The target phosphin-2-en-4-one, equipped with a versatile
enone functionality, represents a novel phosphinane scaffold
potentially amenable to rich chemistry further downstream.
Since the time the enantioselective deprotonation of cyclic
ketones by a chiral lithium amide was first demonstrated in
1986,10a10b the method has been widely utilized in asymmetric
synthesis for generating chirality centers in cyclic ketones by
Received: December 29, 2020
Published: April 26, 2021
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.joc.0c03055
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Figure 1. Reported optically active phosphinanes.
Scheme 1. Designed Desymmetrization Routes to 1-Phenylphosphin-2-en-4-ones 4
desymmetrization.11 Although efficient desymmetrizations of a
number of oxa-, aza-, and thia-heterocyclic ketones by chiral
lithium amides have been already demonstrated,10f1012 the
corresponding P-heterocyclic analogs have not been inves-
tigated before. Thus, we started with checking the viability of
enantioselective deprotonations of 1-phenylphosphinan-4-one
1-oxide (1a), 1-borane (1b), and 1-sulfide (1c) using lithium
amide derived from amine (S,S)-5 as the model base premixed
with an excess of TMSCl before addition of a ketone (ISQ - in
situ quench)13 (Table 1).
sulfide 1c gave the expected enol ethers 2b and 2c, respectively,
albeit in low yields and with very low ee. Subsequent testing of
phosphinanone sulfide 1c revealed that addition of 0.5 equiv. of
LiCl allowed increasing the yield and ee of silyl enol ether 2c to
more acceptable levels (entry 5) and that allowing lithium amide
to react with phosphinanone sulfide 1c before TMSCl was
introduced (EQ - external quench)14 gave slightly better results
than the ISQ alternative (entries 5 and 6). As checked under
these conditions again, the amount of 0.5 equiv. of LiCl was
sufficient; increasing its loading to 1 equiv. did not bring about
improvement of ee.
As shown in Table 1 (entries 1−3), phosphinanone oxide 1a
failed to provide silyl enol ether 2a, whereas borane 1b and
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a
Table 1. Enantioselective Deprotonation of 1 Using Lithium Amide Derived from Amine 5
b
c
no.
X
procedure
additive (equiv.)
yield [%]
ee [%]
1
2
3
4
5
6
7
O
BH3
S
S
S
ISQ
ISQ
ISQ
ISQ
ISQ
EQ
traces
17
18
19
71
n.d.
7
8
HMPA (2)
LiCl (0.5)
LiCl (0.5)
LiCl (1)
4
53
54
52
S
S
76
81
EQ
a
Standard reaction conditions: 1 (0.1 mmol), (S,S)-5 (0.3 mmol, 3 equiv.), n-BuLi (1.6 M solution, 3 equiv.), TMSCl (0.5 mmol, 5 equiv.), in
b
c
THF (2 mL; c = 0.05 mol/L), at −78 °C for 1 h. Determined by 31P NMR. Determined for the crude reaction mixture by CSP-HPLC.
The details of further optimization of these reaction
conditions, which included variations of molarity, stoichiometry,
and temperature, are presented in Table 2.
even accompanied by an increase of enantioselectivity observed
before (cf. entries 10 and 12).
Once the optimization of the reaction conditions was
completed, also other amine catalysts were tested for their
efficiency in desymmetrization of 1-phenylphosphinan-4-ones
1c and 1b. The results obtained with chiral monoamines 5−13,
15, and 16 and diamines 14 and 17−19 are displayed in Table 3.
Inspection of the results collected in Table 3 reveals that the
best enantioselectivities in desymmetrization of phosphinanone
sulfide 1c were achieved with C2-symmetric lithium bis(α-
arylethyl)amides derived from amines (S,S)-5 and (S,S)-6, i.e.,
87 and 76% ee, respectively. The C1-symmetric α-phenylethyl-
amine derived bases 7−12 and 16 were also effective in
desymmetrizing phosphinanone sulfide 1c and gave silyl enol
ether 2c in good yield and with enantioselectivity reaching 59%
ee. Diamines 14 and 17−19 gave slightly lower enantioselectiv-
ities than the monoamines. In turn, desymmetrization of
phosphinanone borane 1b carried out with lithiated 5−19
under the same conditions gave silyl enol ether 2b in generally
better yields but with much lower enantioselectivities than
sulfide 2c. For borane 2b, the best ee’s were again achieved with
lithium amides derived from (S,S)-5 and (S,S)-6, i.e., 61% ee at
95% conversion and 52% ee at 68% conversion, respectively.
Next, we turned our attention to the oxidation of silyl enol
ethers 2b,c required for their conversion into phosphinenones
4b,c. Our initial attempts involved use of the well-known
procedures utilizing Pd(OAc)2 in acetonitrile,15 DDQ in
benzene, and trityl tetrafluoroborate in dichlorometane16 as
the oxidizing agents, but with these reagents, phosphinenones 4
were produced in very low yields (Table 4, entries 1−3).
Subsequent treatment of silyl enol ethers 2c and 2b with ceric
ammonium nitrate (CAN) in DMF17 led to the formation of
phosphinenones 4c and 4a in 69 and 74% yields, respectively
(entries 4 and 5). It should be noted, however, that under these
conditions, phosphinenone borane 4b could not be obtained
due to concurrent oxidation of the P center during the reaction
course. Finally, using Nicolaou et al.’s procedure for the
oxidation of silyl enol ethers to α,β-unsaturated carbonyl
compounds utilizing the IBX·MPO complex as the oxidant,18
phosphinenones 4c and 4a (from 2b) were obtained in high
yields, 80 and 73%, respectively (entries 8 and 9).
Table 2. Optimization of Conditions of Enantioselective
a
Deprotonation of Phosphinanone Sulfide 1c
amine
(equiv.)
n-BuLi
(equiv.)
Cm
temp.
[oC]
yield
b
ee
[%]
c
no.
[mol/dm3]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
1.5
1.5
1.5
2
3
3
3
3
3
3
1.5
1.5
1.5
1.5
1.5
3
3
3
3
0.05
−78
−78
−78
−78
−78
−78
−20
−90
−90
−90
−90
−90
95
63
18
98
85
75
40
77
87
81
85
51
12
54
61
67
74
59
0
83
86
87
86
87
0.025
0.016
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.016
d
1.5
1.5
1.5
d
3
3
a
Standard reaction conditions: 1 (0.1 mmol), (S,S)-5, n-BuLi (1.6 M
solution), LiCl (0.05 mmol), TMSCl (0.5 mmol, 5 equiv.), in THF
b
c
for 1 h. Determined by 31P NMR. Determined for the crude
d
reaction mixture by CSP-HPLC. Reaction run with 1 equiv. of LiCl.
As shown in Table 2, lowering of concentration led to
improvement of enantioselectivity, but unfortunately, it led to a
substantial decrease in yield (entries 1−3). The concentration of
0.025 M was deemed a practical compromise and was then used
in subsequent trials. A substantial increase of enantioselectivity
to 74% ee at 85% conversion was observed when 3 equiv. of
amine 5 was used instead of 1.5 equiv. (entries 4 and 5). In
addition, lowering of the reaction temperature to −90 °C
resulted in further enhancement of enantioselectivity up to 87%
ee at 81% conversion (entry 10). Finally, checking the
concentration factor once again confirmed that its lowering
resulted in a substantial decrease in yield, but this time, it was not
Encouraged by the latter’s promising results and taking into
account the fact that silyl enol ethers 2c and 2b proved to be
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Table 3. Screening of Chiral Amines 5−19 in Desymmetrization of Phosphinanones 1b,c by Enantioselective Deprotonation
a
under Optimized Conditions
a
Standard reaction conditions: 1 (0.1 mmol), chiral amine 5−18 (0.3 mmol, 3 equiv.), n-BuLi (1.6 M solution, 1.5 equiv.), THF (4 mL; c = 0.025
b
c
mol/L), at −78 °C for 1 h, TMSCl (0.5 mmol, 5 equiv.). Determined by 31P NMR. Determined for the crude reaction mixture by CSP-HPLC.
Table 4. Oxidation of Silyl Enol Ethers 2b,c
a
no.
X
oxidizing agent (equiv.)
solvent
conditions
ratio (enone 4/ketone 1)
d
1
2
3
4
5
6
7
8
9
S
S
S
S
BH3
S
BH3
S
BH3
Pd(OAc)2 (1)
DDQ (1.5)
PhC+BF4− (2)
CAN (2.5)
CAN (2.5)
IBX (3)
IBX (3)
IBX·MPO (4)
IBX·MPO (4)
CH3CN
C6H6
DCM
DMF
DMF
DMSO
DMSO
DMSO
DMSO
rt, 10 h
7/93
1/99
5/95
69/31
74/26
21/79
19/81
80/20(67)
73/27 (58)
rt, 1 h
rt, 12 h
0 °C → rt, 2.5 h
0 °C → rt, 2.5 h
40 °C, 12 h
40 °C, 12 h
rt, 2 h
b
b
c
b
c
rt, 2 h
a
b
Determined for the crude reaction mixture by GC−MS and 31P NMR analysis. Identified as oxides 4a and 1a due to P-oxidation occurring under
c
d
the reaction conditions. Isolated yield of enone 4. rt = 18−22 °C.
Scheme 2. One-Pot Synthesis of Phosphinenone 4c on a Preparative 1.1 g (5 mmol) Scale
highly susceptible to hydrolysis during chromatographic
purification, we decided to combine the best desymmetrization
and oxidation protocols found for phosphinanone 1c in a one-
pot process to avoid substantial loss of the intermediate silyl enol
ether during isolation (Scheme 2).
As shown in Scheme 2, the two steps carried out in one flask
without isolation of the intermediate 2c furnished phosphine-
none 4c in overall 49% isolated yield. The determination of
enantiomeric excesses of intermediate silyl enol ether 2c and of
the obtained phosphinenone 4c (CSP-HPLC) revealed that a
slight loss of enantiomeric purity might have taken place during
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Table 5. Preliminary Screening of Reaction Conditions for Conversion of Phosphinanones 1a−c to Phosphinenones 4a−c via
a
Catalytic α-Bromination
b
c
no.
X
solvent
additive (20 mol %)
Br-source
yield 4a,c [%]
ee [%]
1
2
3
4
5
6
7
8
O
O
O
O
O
O
O
O
DCM
THF
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
20
NBS
20
NBS
20
45
74
61
41
42
47
21
10
1
8
DMF
CH3CN
DCM
DCM
DMF
DCM
DCM
DCM
DCM
DCM
DCM
6
AcOH
PhCOOH
PhCOOH
32
34
6
d
76(64)
47
9
O
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
11
10
11
12
13
BH3
BH3
S
traces
57
S
24
a
Standard reaction conditions: NBS (0.15 mmol) was added to a mixture of 1 (0.1 mmol), an additive (20 mol %), and amine catalyst (20 mol %)
b
in the indicated solvent (2 mL) and stirred at room temperature for 16 h and at 60 °C for 0.5 h. Determined by GC−MS and 31P NMR analysis.
c
d
Determined for the crude reaction mixture by CSP- HPLC. Yield of the isolated product in parentheses.
Table 6. Evaluation of Amine Catalysts in Conversion of Phosphinanones 1a,c to Phosphinenones 4a,c via Enantioselective α-
Bromination under Optimized Conditionsa
a
Procedure: To a mixture of 1a or 1c (0.1 mmol), PhCOOH (0.02 mmol), and a catalyst (0.02 mmol) in DCM (2 mL), NBS or 20 (0.15 mmol)
b
was added and the reaction mixture was stirred at room temperature for 16 h and then at 60 °C for 0.5 h. Yields of 4a and 4c determined by GC−
MS analysis. Enantiomeric excess determined for the crude reaction mixture by CSP-HPLC. Reaction run without PhCOOH.
c
d
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a
Table 7. Synthesis of Phosphinenones 4a,c via Organocatalytic Enantioselective α-Chlorination of 1a,c
b
c
no.
X
catalyst
Cl-source
yield 4a,c [%]
ee [%]
c
1
O
O
O
O
O
O
S
O
O
O
(S)-19
(S)-19
(S)-19
(S)-19
(S,S)-25
(S,S)-25
(S,S)-25
(R)-17
(S)-21
(S)-24
NCS
NCS
24
3
rac
rac
rac
rac
30
2
3
c
PhICl2
PhICl2
NCS
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
26
56
34
74
0
91
87
88
4
5
6
7
8
9
10
21
rac
rac
rac
a
Standard reaction conditions: NCS or PhICl2 (0.15 mmol) was added to a mixture of of 1 (0.1 mmol), PhCOOH (20 mol %), and amine catalyst
(20 mol %) in DCM (2 mL) and stirred at rt for 1 day. DBU (1.5 equiv.) was then added, and the reaction mixture was stirred at rt for an
b
c
additional 4 h to effect elimination of HCl. Determined by 31P NMR spectroscopy. Enantiomeric excess determined for the crude reaction
mixture by CSP-HPLC.
the oxidation step. Importantly, however, recrystallization of the
isolated sulfide 4c of 73% ee from hexane/i-PrOH allowed its
enantiomeric purity to increase to 96% ee.
were selected for screening of a number of other chiral amine
catalysts in the next optimization step. The results of this
screening are summarized in Table 6. The reactions of all tested
amines were performed with and without benzoic acid, but only
the better result of these two runs has been listed for clarity.
As can be seen in Table 6, screening of amines 13−17 and
21−24 as the organocatalysts allowed the enantioselectivity of
bromination of phosphinanone 1a to increase only up to 55% ee
when (S)-proline naphthylamide 24 was used as the catalyst.
Interestingly, C2-symmetric 4,5-diphenyl-imidazolidine (25),
the reported most efficient catalyst for enantioselective α-
bromination of cyclic ketones,10g afforded enone 4a of only 28%
ee. Apparently, pyrrolidine based amines performed somewhat
better than other amines tested in the studied α-bromination of
phosphinanone 1a. Surprisingly inefficient were C2-symmetric
diamines even though DACH-derived (R,R)-26 afforded enone
4a of 77% ee but, unfortunately, at nearly negligible 3%
conversion.
Also listed in Table 6 are the results of desymmetrization of
phosphinanone sulfide 1c carried out with compound 20 as the
brominating agent under otherwise the same conditions. These
reactions proceeded relatively well and afforded enone 4c in
good yields (56−84%) but with only moderate enantiomeric
enrichment (8−38% ee). Possibly the best match of yield and
enantiomeric purity of 4c was achieved with DACH derivative
(R,R)-26 (66% and 38% ee, respectively) and with imidazolidine
(S,S)-25 (84% and 33% ee, respectively).
In the second part of our study, we turned our attention to
another organocatalytic strategy expected to be suitable to
achieve our goal. In 2005, Jørgensen et al.10g described the first
enantioselective α-bromination of ketones utilizing N-bromo-
succinimide (NBS) and 4,4-dibromo-2,6-di-tert-butyl-cyclo-
hexa-2,5-dienone (20) as the brominating agents and (S)-
proline and a C2-symmetric imidazolidine as the chiral catalysts.
These reagents enabled the formation of stereogenic C−Br
centers with up to 94% ee in high yields.10g We decided then to
check the viability of this protocol in the asymmetric α-
bromination of phosphinanones 1a,c, which, when followed by
elimination of HBr, could lead to the target optically active
phosphinenones 4a,c.
We started our investigations with a brief screening of solvents
and additives in α-bromination of oxide 1a and sulfide 1c, using
NBS (or 20) as the brominating agent and (S)-proline as the
model chiral catalyst. At the outset, we were pleased to find that
elimination of HBr started to occur already under the
bromination conditions and that practically quantitative
elimination of HBr could be achieved by simply raising the
temperature at the end of the reaction to 60 °C for half an hour.
We included this maneuver to the screening conditions to make
the planned synthesis of phosphinenones 4a,c a one-pot process
(Table 5).
As can be seen from the collected data, a change of solvent as
well as an added acid19 can strongly influence the outcome of the
reaction (Table 5, entries 7−13). With added benzoic acid, the
enantiomerically enriched 4a was obtained with 34% ee and in
47% yield, what constituted a significant improvement over the
reaction run without this additive in the same solvent (DCM)
(cf. entries 7 and 12). In turn, changing the solvent to THF or
DMF resulted in a marked increase of the conversion, but the
observed enantioselectivity was significantly lowered. Thus, the
conditions utilizing DCM and added benzoic acid (entry 12),
which best compromised the conversion and induction levels,
Looking for further improvement, we also decided to briefly
check the efficiency of analogous enantioselective α-chlorina-
tions, which have been recently demonstrated to be highly
efficient in the case of six-membered-ring ketones.10f The results
of screening experiments involving chlorination of phosphina-
nones 1a,c by NCS and PhICl2 in the presence of (S)-proline
and other amine catalysts, followed by DBU-assisted elimination
of HCl from intermediate α-chloro ketone 3-Cl to give enone
4a,c, are collected in Table 7.
The collected data reveal that PhICl2 as the chlorine source
gave better conversions than NCS and that addition of benzoic
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Scheme 3. Attempted Enantioselective Desymmetrization of Phosphinanone 1a through Enamine Oxidation20
acid had a beneficial effect on the overall yield of phosphinenone
4a, especially in combination with PhICl2. Under these
conditions, (S)-proline catalyzed the formation of α-chlor-
ophosphinanone intermediate 3-Cl in moderate yields but,
unfortunately, the resulting enone 4a was formed as a racemate
(entries 1−4). Similarly, chlorinations of phosphinanone 1a
with amines 17, 21, and 24 as the catalysts also led to the
formation of racemic enone 4a, although in these cases with
remarkably high conversions of 91, 87, and 88%, respectively
(entries 8−10). In turn, imidazolidine (S,S)-25, the reported
excellent catalyst for the asymmetric α-chlorination of six-
membered-ring ketones,10f afforded enantioenriched enone 4a
of only 30 (with PhICl2) or 21% ee (with NCS) in moderate
34% and good 74% yields, respectively (entries 5 and 6). It is
important to note, however, that in these two cases, as
determined by comparison of the pertinent CSP-HPLC
chromatograms, the use of (S,S)-25 as the catalyst led to the
formation of enone 4a enriched in the enantiomer opposite to
that found in predominance in 4a obtained by the α-
bromination procedure utilizing the same (S,S)-25 as the
catalyst. Interestingly, an attempted reaction of sulfide 1c under
exactly the same conditions failed completely (entry 7). At this
point, considering that the prospect of getting high enantiose-
lectivity in desymmetrizations of phosphinanones 1a,c by α-
chlorination did not look promising, further optimization of this
process was discontinued. Nonetheless, despite the fact that the
chlorination procedure did not provide the expected improve-
ment of enantioselectivity in the studied syntheses of optically
active phosphinenones 4, the developed one-pot chlorination-
elimination procedure is likely to find use as an effective method
for synthesis of racemic phosphinenone oxide 4a (cf. entries 8−
10).
of phosphinanone sulfide 1c at −90 °C using 3 equiv. of lithium
amide derived from commercially available amine S,S-5.
Subsequent in situ oxidation of the formed enantiomerically
enriched silyl enol ether 2c by IBX·MPO converts it to optically
active phosphinenone 4c, the enantiopurity of which can be
upgraded to 96% ee by recrystallization. Desymmetrization of
phosphinanone oxide 1a can be best achieved by asymmetric α-
bromination using (S)-proline amide 24 as the catalyst to
provide enriched 3-bromophosphinanone 3, which, in turn,
undergoes in situ elimination of HBr to afford phosphinenone
4a of 55% ee in 54% yield. The analogous asymmetric α-
chlorination-elimination procedure offers very low or even no
enantioselectivity in desymmetrization of phosphinanone 1a.
Nevertheless, it allows obtaining phosphinenone oxide 4a in
very high yields (cf. Table 7, entries 8−10) and may thus
constitute a useful route to rac-4a.
EXPERIMENTAL SECTION
■
General Information. All reactions were performed under an
argon atmosphere using Schlenk techniques or in a 10 mL glass reaction
tubes with a screw cap. Only dry solvents were used, and the glassware
was heated under vacuum prior to use. THF was dried over sodium/
benzophenone ketyl. LiCl was dried in a Schlenk tube under vacuum at
150 °C for 5 h. TMSCl, NBS, MPO, DMSO, chiral amines 5, 6, 13, 14,
21, and (S)-proline (19) were purchased from commercial sources and
used without further purification. Solvents for chromatography and
extraction were commercially available and used as received without
further purification. Solvents for crystallization and Et3N were distilled
once before use. Room temperature (rt) means a range of temperatures
from 18 to 22 °C.
The NMR spectra were recorded with a Bruker Ascend (500 MHz)
spectrometer in CDCl3 as a solvent at room temperature unless
otherwise noted. Chemical shifts (δ) are given in ppm relative to
tetramethylsilane (1H), residual CHCl3 (13C), or external 85% H3PO4
(31P) as a reference. The following abbreviations are used in reporting
NMR data: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), br (broad). Coupling constants (J) are in Hz. High-
resolution mass spectrometry analyses were obtained on a Shimadzu
LCMS IT - TOF spectrometer. Elementary analyses were performed on
a PerkinElmer CHN 2400 analyzer. Melting points were determined on
All in all, it is tempting to conclude that enantioselective α-
halogenation of phosphinanone 1, a six-membered-ring ketone
possessing a phosphorus function in the γ position, is
considerably more challenging than the parent cyclohexanone
and related six-membered-ring ketones.,10f10g Moreover, a poor
result of our attempted organocatalytic desymmetrization of
phosphinanone oxide 1a via enamine oxidation under recently
reported optimized conditions20 shown to be effective in
converting a whole variety of mono and doubly 4-substituted
cyclohexanones to the corresponding cyclohexenones of very
high enantiomeric purity corroborates this notion further
(Scheme 3).
a Buchi Melting Point M - 560 in a capillary tube and are uncorrected.
̈
Mass spectra were recorded with a GC−MS spectrometer working in
electron ionization (EI) mode. Chiral HPLC analysis was performed on
a Shimadzu HPLC using Chiralcel columns. Optical rotations were
measured on a PerkinElmer 341LC spectrometer using a 1 mL cell with
a 10 mm path length and are reported as follows: [α]2D0 (c g/100 mL,
solvent). Thin layer chromatography (TLC) was performed with
precoated silica gel plates and visualized by potassium permanganate
(KMnO4) staining or exposing to iodine vapor. The reaction mixtures
were purified by column chromatography over silica gel (60−240
mesh). The chiral amines 7−12,21 15−16,22 17,23 18,24 25,25 26,26
27,27 and 28−3028 were prepared according to the literature
procedures. Analytical data for those amines are in accordance with
those previously reported. The reagents IBX29 and 4,4-dibromo-2,6-di-
tert-butyl-cyclohexa-2,5-dienone (20)30 were synthesized according to
reported procedures, and their properties matched those previously
reported.
CONCLUSIONS
■
Even though the asymmetric deprotonation and asymmetric
halogenation of phosphinanone 4 have turned out to be less
efficient than those of carbocyclic ketones, the developed one-
pot enolization-oxidation and halogenation-elimination proce-
dures have for the first time provided access to the new P-
stereogenic phosphin-2-en-4-one derivatives in nonracemic
forms. A good level of asymmetric induction (87% ee at 81%
conversion) can be achieved by enantioselective deprotonation
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Synthesis of Substrates (1a, 1b, and 1c). 1-Phenylphosphinan-
4-one 1-oxide (1a), 1-borane (1b), and 1-sulfide (1c) were prepared
from the free phosphine (1-phenylphosphinan-4-one) according to the
modified literature procedure.31 A dry, argon-flushed Schlenk-flask,
equipped with a magnetic stirrer and a septum, was charged with 1-
phenylphosphinan-4-one (1.92 g, 0.01 mol) and dry solvent (15 mL).
The solution was cooled to 0 °C when hydrogen peroxide (0.012 mol),
borane-tetrahydrofuran (0.013 mol), or elemental sulfur (0.0105 mol)
was slowly added to it. After 45 min at 0 °C, the solution was allowed to
warm to room temperature and stirred for 24 h. The solution was
evaporated, and the residue was recrystallized from Et2O or Et2O/
hexane (1:2). The physical and spectral data for 1-phenylphosphinan-4-
one 1-oxide (1a) and 1-phenylphosphinan-4-one 1-sulfide (1c) are in
accordance with those previously reported.31,32 Analytical data for 1-
phenylphosphinan-4-one 1-borane (1b) are described below.
General Experimental Procedure for the Desymmetrization
of 1-Phenylphosphinan-4-ones by Enantioselective Enoliza-
tion.14 The synthesis of silyl enol ethers 2b and 2c (the external quench
procedure (EQ)) is as follows. In a flame-dried Schlenk tube (20 mL)
equipped with a magnetic stirrer and inert gas inlet, the lithium amide
base was formed by addition of n-BuLi (0.19 mL, 1.6 mol/dm3 solution
in hexanes; 0.49 mL, 0.15 mmol) to a solution of the chiral secondary
amine (0.3 mmol) and LiCl (2.1 mg, 0.05 mmol) in THF (4 mL) under
nitrogen at −78 °C (dry ice/acetone bath). After 5 min, the solution
was allowed to warm to room temperature and then recooled to −90 °C
(methanol/liquid nitrogen bath) before addition of a solution of 1-
phenylphosphinan-4-one 1-sulfide (1c) or 1-phenylphosphinan-4-one
1-borane (1b) (0.1 mmol) in THF (1 mL). After 30 min, Me3SiCl
(0.063 mL, 0.5 mmol) was added to the reaction mixture, which was
then stirred at −90 °C for further 45 min. After that time, the solution
was allowed to warm to room temperature and the solvent was
evaporated. The residue was quickly purified on a silica gel column
(hexane/THF = 6:1) to give silyl enol ether 2b or 2c as a colorless oils.
2b and 2c are highly susceptible to hydrolysis under extraction and
column chromatography conditions, and the reported yields and
enantiomeric excesses refer to those determined for crude products.
Enantiomeric excess of 2b and 2c was determined by HPLC analysis on
a Chiralcel AS-H column using hexane/i-PrOH (90/10).
General Procedure for the Organocatalytic α-Halogenation
of 1-Phenylphosphinan-4-ones. In a flame-dried Schlenk tube (10
mL) equipped with a magnetic stirrer, the halogenating agent ((NBS,
20, NCS, or PhICl2) (0.15 mmol)) was added to a mixture of
phosphinanone 1a or 1c (21 or 22 mg, respectively, 0.1 mmol),
PhCOOH (2.4 mg, 0.02 mmol), and organocatalyst (0.02 mmol) in
DCM (2 mL) at 0 °C (ice/water bath), and the reaction mixture was
allowed to warm to room temperature and stirred for further 16 or 24 h
at that temperature. Then, in chlorination reactions, DBU (22.8 mg,
0.15 mmol) was added to effect elimination of HCl from the
intermediate chloro ketone 3-Cl, and the reaction mixture was stirred
at room temperature for 1 h. In bromination reactions, the reaction
mixture was warmed up to 60 °C (heating mantle) for 30 min to
complete quantitative elimination of HBr from the intermediate bromo
ketone 3. Then, evaporation of the reaction mixture gave crude enone
4a or 4c. The crude products could be purified on a silica gel column
using either DCM/THF = 10:1 for enone 4a or hexane/THF = 8:1 for
enone 4c to give the pure products as colorless oils. Yields of 4a and 4c
were determined by GC−MS analysis and confirmed by 31P NMR
spectroscopy. Enantiomeric excess was determined by HPLC analysis
using CSP.
One-Pot Procedure for Direct Synthesis of Phosphin-2-en-4-
one 4c from Phosphinanone 1c. In a flame-dried Schlenk tube (400
mL) equipped with a magnetic stirrer and inert gas inlet, the lithium
amide base was formed by addition of n-BuLi (1.6 mol/dm3 solution in
hexanes; 4.6 mL, 7.37 mmol) to a solution of (−)-bis[(S)-1-
phenylethyl]amine (S,S-5) (3.38 mL, 14.73 mmol, 3 equiv.) and LiCl
(104 mg, 2.46 mmol, 0.5 equiv.) in THF (200 mL) under nitrogen at
−78 °C (dry ice/acetone bath). After 5 min, the solution was allowed to
warm to room temperature and then recooled to −90 °C before
addition of a solution of 1c (1.1 g, 5 mmol) in THF (20 mL). After 30
min, Me3SiCl (3.1 mL, 24.5 mmol, 5 equiv.) was added to the reaction
mixture, which was then stirred at −90 °C (methanol/liquid nitrogen
bath) for further 45 min. After this time, the solution was allowed to
warm to room temperature and the solvent was evaporated (during the
evaporation, the temperature of the solution should be kept below 25
°C) to give crude silyl enol ether 2c. The silyl enol ether 2c was
obtained in 82% yield (determined by 31P NMR spectroscopy) and
with an enantiomeric excess of 76% (determined by chiral HPLC
analysis using a Chiralcel AS-H column). Then, following the published
oxidation protocol,18 equimolar amounts of IBX and MPO (2.06 g of
IBX and 0.92 g of MPO, 1.5 equiv.) dissolved in DMSO (5 mL) were
added in one portion at room temperature to the crude vacuum-dried
silyl enol ether 1c dissolved in 3 mL of DMSO. The solution was stirred
vigorously for 2 h at room temperature. After this time, the reaction
mixture was diluted with aqueous HCl (5%) and extracted with DCM
(five times). The combined organic phase was dried (MgSO4), and the
solvent was removed in vacuum to afford the crude product, which was
further purified by silica gel column chromatography (hexane/THF =
6:1) to give enone 4c as a light yellow oil in 48% overall yield (two
steps) (0.52 g, 2.4 mmol) and with 73% ee (determined by HPLC
analysis using a Chiralcel OJ-H column). Repeated recrystallizations
(three times) of (−)-4c (73% ee) from a hexane/i-PrOH mixture
allowed to increase its enantiopurity of the levorotatory enantiomer of
4c left in the mother liquor up to 96% ee.
Catalytic Desymmetrizing Dehydrogenation of Phenyl-
phosphin-2-en-4-ones through Enamine Oxidation. Reactions
were performed according to the literature procedure20 at room
temperature. To a 10 mL flask were added phenylphosphinan-4-one
1a−c (0.041−0.045 g, 0.2 mmol), catalyst (20 mol %, 0.04 mmol),
pentanedioic acid (7.3 mg, 30 mol %, 0.06 mmol), and diethyl ether
(0.1 mL). The reaction system was gently stirred for half an hour. Then
IBX (56 mg, 0.2 mmol) was added followed by 0.1 mL of diethyl ether.
After 48 h, the reaction system was diluted with ether and immediately
passed through a thin layer of silica gel. The remaining organic phase
was concentrated in vacuum. Yield was determined by 31P NMR
analysis, and enantiomeric excess was determined by CSP-HPLC
analysis.
1-Phenylphosphinan-4-one 1-Oxide (1a). This compound was
prepared according to the general procedure from 1-phenylphos-
phinan-4-one (1.92 g, 0.01 mol) and hydrogen peroxide (30% solution
in water, 1.36 mL, 0.012 mol), in acetone (15 mL). The reaction gave
the corresponding oxide as the crystalline adduct 1a4·(H2O2)3; Anal.
Found: C, 56.8; H, 6.61. The adduct was practically insoluble in
common organic solvents such as THF, DCM, and acetone. The
formation of this type of adduct of phosphine oxides was previously
reported.33 To decompose the adduct and remove H2O2 from 1a, the
formed crystals were melted under vacuum and heated at 180 °C
(heating mantle) for 30 min to give 1.85 g (89%) of pure 1a as white
crystals, mp = 164.8−166.0 °C (lit. 164−165 °C).34 Rf = 0.16 (DCM/
1
THF = 6:1). H NMR (500 MHz, CDCl3): δ 7.83−7.76 (m, 2H),
7.64−7.59 (m, 1 H), 7.58−7.52 (m, 2H), 3.24−3.11 (m, 2 H), 2.80−
2.66 (m, 2H), 2.46−2.31 (m, 4H). 13C{1H} NMR (126 MHz, CDCl3):
δ 207.6 (d, J = 8.2 Hz, C=O), 132.6 (d, J = 2.7 Hz, Cpara), 131.1 (d, J =
99.0 Hz, Cipso), 130.1 (d, J = 9.1 Hz, Cortho), 129.1 (d, J = 11.8 Hz,
Cmeta), 36.4 (d, J = 6.4 Hz, C3,5), 27.2 (d, J = 66.0 Hz, C2,6). 31P{1H}
NMR (202 MHz, CDCl3): δ 28.9 ppm. GC−MS (EI, 70 eV) m/z =
208.0 (10), 181.0 (10), 180.0 (100), 152.0 (46), 151.0 (13), 134.0
(29), 125.0 (80), 124.0 (86), 105.1, (37), 96.0 (13), 91.1 (12). Anal.
Calcd for C11H13O2P: C, 64.13; H, 7.83. Found: C, 64.09; H, 7.88.
1-Phenylphosphinan-4-one 1-Borane (1b). This compound was
prepared according to the general procedure from 1-phenylphos-
phinan-4-one (1.92 g, 0.01 mol) and H3B·THF (1.0 M solution in
THF, 13 mL, 0.013 mol, 1.3 equiv.) in THF (15 mL) at room
temperature for 5 h. Then, after evaporation of solvent, the product was
recrystallized from hexane/Et2O to yield 1.69 g (82%) of 1b as colorless
crystals; mp = 94.1−96.9 °C; Rf = 0.3 (hexane/THF = 8:1). 1H NMR
(500 MHz, CDCl3): δ 7.82−7.75 (m, 2 H), 7.61−7.51 (m, 3H), 3.03−
2.93 (m, 2H), 2.79−2.67 (m, 2H), 2.50−2.38 (m, 2H), 2.37−2.28 (m,
2H), 1.25−0.50 (bm, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 207.3
(d, J = 6.4 Hz, C=O), 132.0 (d, J = 2.7 Hz, Cpara), 131.2 (d, J = 9.1 Hz,
Cortho), 129.3 (d, J = 10.0 Hz, Cmeta), 127.8 (d, J = 53.6 Hz, Cipso), 36.8
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(d, J = 4.5 Hz, C3,5), 22.3 (d, J = 34.5 Hz, C2,6). 31P{1H} NMR (202
MHz, CDCl3): δ 3.2−1.9 (m) ppm. GC−MS (EI, 70 eV) m/z = 192.05
(64), 191.05 (31), 136.05 (18), 125.05 (21), 109.05 (21), 108.05
(100), 107.05 (52), 91.10 (19). Anal. Calcd for C11H16BOP: C, 64.13;
H, 7.83. Found: C, 64.10; H, 7.85.
70.8 Hz, C6). 31P{1H} NMR (202 MHz, CDCl3): δ 16.9 ppm. GC−MS
(EI, 70 eV) m/z = 178.00 (33), 150.00 (19), 132.05 (10), 131.05
(100), 124.00 (24), 103.05 (14). Anal. Calcd for C11H11O2P: C, 64.08;
H, 5.38. Found: C, 64.01; H, 5.24.
1-Phenylphosphin-2-en-4-one 1-Oxide (−)-4a. This compound
was prepared according to the general organocatalytic α-halogenation
procedure from 1a (0.19 g, 1 mmol) to give 0.1 g, (54%) of (−)-4a as
colorless crystals; ([α]2D0 = −152.4 (c 1.1, CHCl3) for ee = 54%); mp =
110.7−113.6 °C; Rf = 0.33 (CHCl3/THF = 10:1). CSP-HPLC
conditions: Chiralcel OD-H, hexane/2-propanol = 90:10, 1 mL/min,
retention time = 27.8 min for the major enantiomer and 32.3 min for
the minor enantiomer. 1H NMR (500 MHz, CDCl3): δ 7.79−7.74 (m,
2H), 7.65−7.60 (m, 1H), 7.58−7.48 (m, 2H), 7.10−7.04 (m, 1H), 6.73
(dd, J = 13.6 and 23.0 Hz, 1H), 3.15 (s, 1H), 2.85−2.73 (m, 1H), 2.62−
2.51 (m, 1H), 2.49−2.40 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3):
δ 196.1 (d, J = 14.5 Hz, C=O), 142.6 (C3), 138.2 (d, J = 83.6 Hz, C2),
132.9 (d, J = 2.7 Hz, Cpara), 130.6 (d, J = 10.9 Hz, Cortho), 129.9 (d, J =
105.4 Hz, Cipso), 129.2 (d, J = 12.7 Hz, Cmeta), 33.8 (d, J = 6.4 Hz, C5),
26.6 (d, J = 70.8 Hz, C6). 31P{1H} NMR (202 MHz, CDCl3): δ 16.9
ppm. GC−MS (EI, 70 eV) m/z = 178.00 (33), 150.00 (19), 132.05
(10), 131.05 (100), 124.00 (24), 103.05 (14). Anal. Calcd for
C11H11O2P: C, 64.08; H, 5.38. Found: C, 64.27; H, 5.43.
1-Phenylphosphin-2-en-4-one 1-Sulfide (rac-4c). This compound
was prepared according to the general one-pot procedure from 1c (0.41
g, 2 mmol) to give 0.19 g, 0.86 mmol, 51% overall yield after two steps,
as colorless crystals; mp = 91.9−92.4 °C; Rf = 0.36 (hexane/THF =
6:1). 1H NMR (500 MHz, CDCl3): δ 7.96−7.89 (m, 2H), 7.66−7.61
(m, 1H), 7.61−7.55 (m, 2H), 7.05−6.95 (m, 1H), 6.63 (dd, J = 12.5
and 34.5 Hz, 1H), 3.30 (tdd, J = 4.6, 12.2 and 16.5 Hz, 1H), 2.95−2.73
(m, 2H), 2.62−2.49 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ
195.6 (d, J = 13.6 Hz, C=O), 139.3 (d, J = 3.6 Hz, C3), 139.2 (d, J = 68.2
Hz, C2), 132.7 (d, J = 3.6 Hz, Cpara), 131.1 (d, J = 11.8 Hz, Cortho), 129.6
(d, J = 85.7 Hz, Cipso), 129.1 (d, J = 11.8 Hz, Cmeta), 34.0 (d, J = 7.3 Hz,
C5), 31.3 (d, J = 55.4 Hz, C6). 31P{1H} NMR (202 MHz, CDCl3): δ
21.3 ppm. GC−MS (EI, 70 eV) m/z = 223.05 (13), 222.05 (100),
190.10 (14), 189.10 (86), 171.10165.05 (10), (12), 143.15 (12),
142.15 (96), 141.15 (18), 140.05 (50), 134.10 (22), 133.10 (50),
131.10 (20), 109.10 (11), 108.10 (28), 107.10 (69), 105.15 (24),
103.10 (18), 91.10 (10), 83.05 (12), 81.05 (11). Anal. Calcd for
C11H11OPS: C, 59.45; H, 4.99. Found: C, 59.39; H, 4.95.
1-Phenylphosphin-2-en-4-one 1-Sulfide (−)-4c. The compound
(−)-4c was prepared according to the general one-pot procedure from
1c (1.1 g, 5 mmol) to give 0.52 g, 2.4 mmol, 48% overall yield after two
steps; colorless oil; ([α]D20 = −86.17 (c 1.5, CHCl3) for ee = 96%); Rf =
0.36 (hexane/THF = 6:1); CSP-HPLC conditions: Chiralcel OJ-H,
hexane/2-propanol = 95:5, 1 mL/min, retention time = 66 min for the
minor enantiomer and 70 min for the major enantiomer. 1H NMR (500
MHz, CDCl3): δ 7.96−7.89 (m, 2H), 7.66−7.61 (m, 1H), 7.61−7.55
(m, 2H), 7.05−6.95 (m, 1H), 6.63 (dd, J = 12.5 and 34.5 Hz, 1H), 3.30
(tdd, J = 4.6, 12.2 and 16.5 Hz, 1H), 2.95−2.73 (m, 2H), 2.62−2.49 (m,
1H). 13C{1H} NMR (126 MHz, CDCl3): δ 195.6 (d, J = 13.6 Hz,
C=O), 139.3 (d, J = 3.6 Hz, C3), 139.2 (d, J = 68.2 Hz, C2), 132.7 (d, J
= 3.6 Hz, Cpara), 131.1 (d, J = 11.8 Hz, Cortho), 129.6 (d, J = 85.7 Hz,
Cipso), 129.1 (d, J = 11.8 Hz, Cmeta), 34.0 (d, J = 7.3 Hz, C5), 31.3 (d, J =
55.4 Hz, C6). 31P{1H} NMR (202 MHz, CDCl3): δ 21.3 ppm. GC−MS
(EI, 70 eV) m/z = 223.05 (13), 222.05 (100), 190.10 (14), 189.10
(86), 171.10165.05 (10), (12), 143.15 (12), 142.15 (96), 141.15 (18),
140.05 (50), 134.10 (22), 133.10 (50), 131.10 (20), 109.10 (11),
108.10 (28), 107.10 (69), 105.15 (24), 103.10 (18), 91.10 (10), 83.05
(12), 81.05 (11). Anal. Calcd for C11H11OPS: C, 59.45; H, 4.99.
Found: C, 59.15; H, 4.78.
1-Phenylphosphin-2,5-dien-4-one 1-Oxide (31a). This compound
was prepared according to the catalytic desymmetrizing dehydrogen-
ation procedure from 1-phenylphosphinan-4-one 1a. 31a: 8 mg, 0.004
mmol, (2%); pale yellow crystals; mp = 131.2−132.6 °C (lit. 130−131
°C);35 Rf = 0.45 (DCM/THF = 6:1); 1H NMR (500 MHz, CDCl3): δ
7.81−7.75 (m, 2H), 7.64 (dd, J = 1.7 and 7.4 Hz, 1H), 7.59−7.54 (m,
2H), 7.16−7.09 (m, 2H), 6.93−6.88 (m, 1H), 6.86−6.81 (m, 1H).
13C{1H} NMR (126 MHz, CDCl3): δ 183.0 (d, J = 25.0 Hz, C=O),
140.4 (d, J = 2.7 Hz, C3,5), 137.8 (d, J = 90.5 Hz, C2,6), 133.2 (d, J =
1-Phenylphosphinan-4-one 1-Sulfide (1c). This compound was
prepared according to the general procedure from 1-phenylphos-
phinan-4-one (1.92 g, 0.01 mol) and elemental sulfur (0.335 g, 0.0105
mol, 1.05 equiv.), in toluene (15 mL). Then, after evaporation of
solvent, the product was recrystallized from Et2O to yield 2.04 g (91%)
of 1c as white crystals; mp = 142.3−145.7 °C (lit. 144−145 °C);34 Rf =
0.26 (hexane/THF = 6:1); 1H NMR (500 MHz, CDCl3): δ 8.00−7.92
(m, 2H), 7.64−7.54 (m, 3H), 3.41−3.26 (m, 2H), 2.82−2.67 (m, 4H),
2.42−2.27 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 207.0 (d, J =
7.3 Hz, C=O), 132.4 (d, J = 2.7 Hz, Cpara), 130.6 (d, J = 10.9 Hz, Cortho),
130.5 (d, J = 80.2 Hz, Cipso), 129.1 (d, J = 11.8 Hz, Cmeta), 36.8 (d, J =
5.5 Hz, C3,5), 31.2 (d, J = 50.9 Hz, C2,6). 31P{1H} NMR (202 MHz,
CDCl3): δ 32.0 ppm. GC−MS (EI, 70 eV) m/z = 224.05 (100), 225.05
(13), 196.00 (27), 191.10 (24), 168.05 (35), 157.05 (12), 141.05 (13),
140.05 (40), 135.05 (13), 133.05 (17), 125.05 (15), 113.05 (20),
109.10 (18), 108.05 (28), 107.05 (46), 105.10 (45), 91.10 (23), 84.10
(12), 83.10 (41). Anal. Calcd for C11H13OPS: C, 58.91; H, 5.84.
Found: C, 58.86; H, 5.85.
1-Phenyl-4-[(trimethylsilyl)oxy]-1,2,3,6-tetrahydrophosphinine
1-Borane (2b). This compound was prepared according to the general
enantioselective enolization procedure from 1b (21 mg, 0.1 mmol) to
give 5 mg (22%) of 2b as a colorless oil. Due to its very high
susceptibility to hydrolysis under column chromatography conditions,
borane 2b was analyzed and used for oxidation studies only as crude; Rf
= 0.72 (hexane/THF = 8:1); 1H NMR (500 MHz, CDCl3): δ 7.77−
7.72 (m, 2H), 7.55−7.45 (m, 3H), 5.08 (dt, J = 4.4 Hz and 18.6 Hz,
1H), 2.7−2.65 (m, 2H), 2.45−2.35 (m, 1H), 2.20−2.05 (m, 3H), 1.1−
0.4 (bm, 3H), 0.21 (t, J = 3.3 Hz, 9H). 13C{1H} NMR (126 MHz,
CDCl3): δ 151.5 (d, J = 12.7 Hz, C4), 131.3 (d, J = 11.8 Hz, Cmeta),
131.3 (d, J = 6.4 Hz, Cpara), 128.9 (d, J = 10 Hz, Cortho), 128.8 (d, J =
51.8 Hz, Cipso), 99.1 (d, J = 8.2 Hz, C5), 26.0 (d, J = 6.4 Hz, C3), 20.3
(d, J = 34.5 Hz, C6), 19.7 (d, J = 36.4 Hz, C2), 0.3 (C-Si). 31P{1H}
NMR (202 MHz, CDCl3): δ −3.7 ppm. GC−MS (EI, 70 eV) m/z =
265.10 (22), 264.10 (100), 263.10 (45), 249.10 (30), 236.05 (48),
221.05 (11), 190.10 (45), 173.05 (44), 155.10 (35), 141.10 (15),
137.05 (11), 135.10 (17), 133.05 (10), 128.10 (12), 127.05 (75),
121.10 (12), 109.05 (23), 107.05 (17), 91.10 (14), 85.10 (28).
1-Phenyl-4-[(trimethylsilyl)oxy]-1,2,3,6-tetrahydrophosphinine
1-Sulfide (2c). This compound was prepared according to the general
enantioselective enolization procedure from 1c (22 mg, 0.1 mmol) to
give 8 mg (31%) of 2c as a colorless oil. Due to its very high
susceptibility to hydrolysis under column chromatography conditions,
sulfide 2c was analyzed and used for oxidation studies only as crude; Rf
= 0.63 (hexane/THF = 6:1); 1H NMR (500 MHz, CDCl3): δ 7.93−
7.88 (m, 2H), 7.55−7.48 (m, 3 H), 5.01 (dt, J = 4.50 and 26.00 Hz,
1H), 3.11−3.00 (m, 1H), 2.88−2.77 (m, 1H), 2.66−2.53 (m, 1H),
2.47−2.35 (m, 1H), 2.33−2.15 (m, 2H), 0.20 (s, 9H). 13C{1H} NMR
(126 MHz, CDCl3): δ 151.4 (d, J = 15.4 Hz, C4), 132.0 (d, J = 78.1 Hz,
Cipso), 131.7 (d, J = 3.6 Hz, Cpara), 130.4 (d, J = 10.0 Hz, Cortho), 128.8
(d, J = 11.8 Hz, Cmeta), 99.3 (d, J = 8.2 Hz, C5), 29.8 (d, J = 54.5 Hz,
C6), 29.1 (d, J = 51.8 Hz, C2), 27.7 (d, J = 7.3 Hz, C3), 0.3 (C-Si).
31P{1H} NMR (202 MHz, CDCl3): δ 27.2 ppm. GC−MS (EI, 70 eV)
m/z = 296.90 (22), 295.90 (55), 262.90 (16), 156.00 (28), 155.00
(100), 91.00 (13).
1-Phenylphosphin-2-en-4-one 1-Oxide (rac-4a). This compound
was prepared according to the general organocatalytic α-halogenation
procedure from 1a (0.57 g, 3 mmol) to give 0.36 g (64%) of rac-4a as
colorless crystals; mp = 106.7−107.3 °C, Rf = 0.33 (CHCl3/THF =
10:1). 1H NMR (500 MHz, CDCl3): δ 7.79−7.74 (m, 2H), 7.65−7.60
(m, 1H), 7.58−7.48 (m, 2H), 7.10−7.04 (m, 1H), 6.73 (dd, J = 13.6
and 23.0 Hz, 1H), 3.15 (s, 1H), 2.85−2.73 (m, 1H), 2.62−2.51 (m,
1H), 2.49−2.40 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 196.1
(d, J = 14.5 Hz, C=O), 142.6 (C3), 138.2 (d, J = 83.6 Hz, C2), 132.9 (d,
J = 2.7 Hz, Cpara), 130.6 (d, J = 10.9 Hz, Cortho), 129.9 (d, J = 105.4 Hz,
Cipso), 129.2 (d, J = 12.7 Hz, Cmeta), 33.8 (d, J = 6.4 Hz, C5), 26.5 (d, J =
6203
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Article
2.7 Hz, Cpara), 130.9 (d, J = 10.9 Hz, Cortho), 129.3 (d, J = 13.6 Hz,
Cmeta), 127.7 (d, J = 111.5 Hz, Cipso). 31P{1H} NMR (202 MHz,
CDCl3): δ −1.3 ppm. GC−MS (EI, 70 eV) m/z = 158.0 (14), 157.0
(100), 150.0 (15), 147.0 (20), 131.0 (13), 129.0 (33), 128.0 (17),
124.0 (14), 103.0 (12), 77.0 (52), 51.0 (37), 50.0 (11), 47.0 (20). Anal.
Calcd for C11H9O2P: C, 64.71; H, 4.44. Found: C, 64.80; H, 4.59.
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Pietrusiewicz, K. M. New Monodentate P,C-Stereogenic Bicyclic
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c03055.
■
sı
Table S1 - Complete catalyst screening of enantioselective
α-bromination of 1a and 1c; Table S2 - Catalytic
desymmetrizing dehydrogenation of 1a−c through
enamine oxidation; Figure S1 - CSP-HPLC traces of
optically active 4c; 1H NMR, 13C{1H} NMR, and
31P{1H} NMR spectra (PDF)
(3) (a) Marinetti, A.; Carmichael, D. Synthesis and Properties of
Phosphetanes. Chem. Rev. 2002, 102, 201−230. (b) Marinetti, A.; Jus,
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S.; Genet, J.-P. Investigation into an asymmetric hydrogenation
promoted by rhodium-phosphetane complexes. Tetrahedron Lett.
1999, 40, 8365−8368. (c) Tang, W.; Zhang, X. New Chiral Phosphorus
Ligands for Enantioselective Hydrogenation. Chem. Rev. 2003, 103,
3029−3070. (d) Imamoto, T.; Oohara, N.; Takahashi, H. Optically
Active 1,1′-Di-tert-butyl-2,2′-diphosphetanyl and Its Application in
Rhodium-Catalyzed Asymmetric Hydrogenations. Synthesis 2004,
2004, 1353−1358. (e) Kollár, L.; Keglevich, G. P-Heterocycles as
Ligands in Homogeneous Catalytic Reactions. Chem. Rev. 2010, 110,
4257−4302.
AUTHOR INFORMATION
Corresponding Author
■
K. Michał Pietrusiewicz − Department of Organic Chemistry,
Institute of Chemical Sciences, Faculty of Chemistry, Marie
Curie-Sklodowska University, 20-614 Lublin, Poland;
orcid.org/0000-0003-0969-4689;
(4) (a) Kobayashi, S.; Shiraishi, N.; Lam, W. W.-L.; Manabe, K.
Asymmetric synthesis of proline and pipecolic acid phosphorous
analogues using enantioselective deprotonation−carboxylation reac-
tions. Tetrahedron Lett. 2001, 42, 7303−7306. (b) Ostermeier, M.;
Prieß, J.; Helmchen, G. Mono- and Bidentate PhosphinanesNew
Chiral Ligands and Their Application in Catalytic Asymmetric
Hydrogenations. Angew. Chem., Int. Ed. 2002, 41, 612−614. (c) Yan,
Y.; Zhang, X. Six-membered bis(azaphosphorinane), readily available
ligand for highly enantioselective asymmetric hydrogenations. Tetrahe-
dron Lett. 2006, 47, 1567−1569. (d) Doro, F.; Lutz, M.; Reek, J. N. H.;
Spek, A. L.; van Leeuwen, P. W. N. M. P-Chirogenic Benzo-Fused
Phenoxaphosphane: Synthesis, Resolution and Study of the Stereo-
chemical Properties of the Corresponding Palladium Complexes. Eur. J.
Inorg. Chem. 2008, 1309−1317. (e) Harvey, J. S.; Malcolmson, S. J.;
Dunne, K. S.; Meek, S. J.; Thompson, A. L.; Schrock, R. R.; Hoveyda, A.
H.; Gouverneur, V. Enantioselective Synthesis of P-Stereogenic
Phosphinates and Phosphine Oxides by Molybdenum-Catalyzed
Asymmetric Ring-Closing Metathesis. Angew. Chem., Int. Ed. 2009,
48, 762−766. (f) Ujj, V.; Kerenyi, A.; Laki, A.; Fogassy, E.; Keglevich,
G. Optically Active 6-Membered P-Heterocycles: 1-Phenyl-1,2-
Dihydrophosphinine Oxide and 1-Phenyl-3-Diphenylphosphinoyl-
1,2,3,6-Tetrahydrophosphinine Oxide. Lett. Org. Chem. 2010, 7,
110−113. (g) Bagi, P.; Laki, A.; Keglevich, G. Preparation of Optically
Active Six-Membered P-Heterocycles: A 3-Phosphabicyclo[3.1.0]
hexane 3-oxide, a 1,2-Dihydrophosphinine 1-oxide, and a 1,2,3,6-
Tetrahydrophosphinine 1-oxide. Heteroat. Chem. 2013, 24, 179−186.
Email: kazimierz.pietrusiewicz@poczta.umcs.lublin.pl
Authors
Elzbieta Łastawiecka − Department of Organic Chemistry,
̇
Institute of Chemical Sciences, Faculty of Chemistry, Marie
Curie-Sklodowska University, 20-614 Lublin, Poland;
orcid.org/0000-0001-6546-1519
Sławomir Frynas − Department of Organic Chemistry, Institute
of Chemical Sciences, Faculty of Chemistry, Marie Curie-
Sklodowska University, 20-614 Lublin, Poland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c03055
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Ministry of Science and Higher
Education (research grant no. N N204 445240) is kindly
acknowledged.
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