Palladium-catalyzed synthesis of a phosphine oxide with a chiral phosphorus center via C-H phosphination

Article abstract of DOI:10.3987/COM-12-12595

A new phosphine oxide with a chiral phosphine center was synthesized from a bis(biphenyl)phosphine oxide by dehydrogenative intramolecular cyclization via P-H and C-H bond activation under palladium catalysis. The absolute configuration of one enantiomer of the phosphine oxide was determined by single crystal X-ray structure analysis. By reducing the phosphine oxide, the corresponding phosphine, which also has a chiral center, was produced. The phosphine compounds could be optically resolved by chiral HPLC column chromatography.

Full text of DOI:10.3987/COM-12-12595

HETEROCYCLES, Vol. 85, No. 12, 2012
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HETEROCYCLES, Vol. 85, No. 12, 2012, pp. 3029 - 3034. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 1st October, 2012, Accepted, 25th October, 2012, Published online, 30th October, 2012
DOI: 10.3987/COM-12-12595
PALLADIUM-CATALYZED SYNTHESIS OF A PHOSPHINE OXIDE
WITH A CHIRAL PHOSPHORUS CENTER VIA C-H PHOSPHINATION
Yoichiro Kuninobu,*† Kazuki Origuchi, and Kazuhiko Takai*
Division of Chemistry and Biotechnology, Graduate School of Natural Science and
Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama
7
00-8530, Japan
†
Present address: Graduate School of Pharmaceutical Sciences, The University of
Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Abstract – A new phosphine oxide with a chiral phosphine center was synthesized
from a bis(biphenyl)phosphine oxide by dehydrogenative intramolecular
cyclization via P-H and C-H bond activation under palladium catalysis. The
absolute configuration of one enantiomer of the phosphine oxide was determined
by single crystal X-ray structure analysis. By reducing the phosphine oxide, the
corresponding phosphine, which also has a chiral center, was produced. The
phosphine compounds could be optically resolved by chiral HPLC column
chromatography.
Chiral phosphine compounds are an important category of organic compounds and there have been many
1
reports on their synthesis. Many chiral phosphine compounds are employed as chiral ligands for
transition metals. Monodentate chiral phosphine ligands are also well known in which the chiral center at
2
the phosphorus atom controls the enantioselectivity.
We have previously reported the
palladium-catalyzed synthesis of phosphafluorene oxides from secondary biarylphosphine oxides by
3
intramolecular dehydrogenative cyclization via P-H and C-H bond cleavage (Scheme 1). We anticipated
that this reaction could be applied to the synthesis of phosphine oxides with a chiral phosphorus center,
followed by reduction of the phosphine oxides to chiral phosphine derivatives. We report herein the
palladium-catalyzed synthesis of a phosphine compound with a chiral center, which could be purified as a
single enantiomer.

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HETEROCYCLES, Vol. 85, No. 12, 2012
Scheme 1. Synthesis of phosphafluorene oxides by intramolecular dehydrogenative cyclization via P-H
and C-H bond cleavage.
2
Treatment of bis(biphenyl)phosphine oxide 1 with a catalytic amount of palladium acetate Pd(OAc) gave
4
phosphafluorene oxide 2 in 75% yield (eq 1). The product 2 has a chiral center and was obtained in
racemic form [1:1 mixture of (R)-2 and (S)-2 isomers]. This indicated that chiral phosphine oxides must
be formed using a palladium catalyst with a chiral ligand. Therefore, we investigated several
2
combinations of Pd(OAc) and chiral phosphine ligands. However, the cyclization reaction did not
proceed, probably due to steric hindrance between the chiral phosphine ligands and 1.
We next investigated the optical resolution of 2 using a chiral HPLC column [Chiralpak IB (2.0 cm I.D. x
2
2
5 cm L, Daicel Chemical Industries, LTD.); eluent: CH
3
CN/ THF = 80/20; flow rate: 7.0 mL/min; temp =
5 °C; det. 300 nm (UV); injection: 9.45 mL (3.3 g/L in eluent)]. As a result, the two enantiomers could be
separated completely (retention times: 2-a, 16.7 min; 2-b, 24.0 min). The structure of enantiomer 2-a was
determined by single crystal X-ray structure analysis (Figure 1), which showed that the absolute
configuration of 2-a is the (S)-form. The specific rotation value of 2-a was -410° (2-b, +410°). Therefore,
it is clear that phosphafluorene oxides 2-a and 2-b are enantiomers.
Figure 1. Single crystal X-ray structure of 2-a.

HETEROCYCLES, Vol. 85, No. 12, 2012
3031
It is well known that phosphine derivatives have trigonal pyramidal structures and stereoinversion of the
phosphorus atoms typically does not occur because of the high energy of the reflecting barrier. Therefore,
it is usually possible to use phosphines with three different substituents in an optically active manner. The
reduction of (S)-2-a with trichlorosilane provided the corresponding phosphine 3 (eq 2). Unfortunately,
5
stereoinversion at the phosphorus center occurred and 3 was obtained as a racemic mixture. Therefore,
optical resolution was again required after the reduction of 2. As a result of the optical resolution of
phosphine 3 using the chiral HPLC column [Chiralpak IB (2.0 cm I.D. x 25 cm L, Daicel Chemical
Industries, LTD.); eluent: hexane/2-propanol = 20/1; flow rate: 7.0 mL/min; temp = 25 °C; det. 300 nm
(UV); injection: 9.45 mL (3.3 g/L in eluent)], two enantiomers (S)-3 and (R)-3 could be obtained in
enantiomerically pure forms (retention times: (S)-3, 12.6 min and (R)-3, 15.5 min).
In summary, we have succeeded in the synthesis of a phosphine oxide with a chiral phosphorus center from
2
a bis(biphenyl)phosphine oxide by treatment with a catalytic amount of a palladium salt, Pd(OAc) . The
obtained phosphine oxide was easily reduced to the corresponding phosphine in racemic form. The
enantiomers of the phosphine oxide and phosphine could be separated completely by a chiral HPLC column.
The structure of one enantiomer of the phosphine oxide was determined by single crystal X-ray structure
analysis. Scope of substrates and the utility of the phosphine compound 3 are not clear at this stage. We
hope that this synthesis of a phosphine oxide with a chiral phosphorus center provides useful insight into
organophosphorus chemistry.
EXPERIMENTAL
General. All reactions were carried out in a dry solvent under an argon atmosphere. THF and
1
,4-dioxane were purchased from Wako Pure Chemical Industries and were dried and degassed before use.
Pd(OAc) was purchased from Aldrich Co. 2-(2-Bromophenyl)naphthalene were prepared by
Suzuki-Miyaura cross-coupling reaction between 2-bromonaphthalene and o-bromophenylboronic acid.
2
6
,7

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HETEROCYCLES, Vol. 85, No. 12, 2012
1
13
31
H (400 MHz), C (100 MHz), and P (162 MHz) NMR spectra were recorded using a JEOL JNM-LA400
spectrometer. Proton chemical shifts are reported relative to Me Si (CDCl ) at  0.00 ppm or residual
4
3
solvent peak (CDCl
Phosphorus chemical shifts are reported relative to an external 85% H
recorded on a SHIMADZU IRAFFINITY-1 100V J.
Typical Procedure for the Synthesis of Bis(biphenyl)phosphine Oxide 1: Magnesium turnings (0.535 g,
0.0 mmol) were suspended in THF (10 mL). A bead of iodine was added to the above mixture, and the
3
at  7.26 ppm). Carbon chemical shifts are reported relative to CDCl
3
at  77.00 ppm.
3
PO at  0.00 ppm. IR spectra were
4
2
mixture was stirred at room temperature until the color of iodine faded. To this mixture was added
dropwise a solution of 2-(2-bromophenyl)naphthalene (5.10 g, 18.0 mmol) in THF (44 mL) over 5 min.
The reaction mixture was stirred at 80 °C for 1 h and was then cool down to room temperature. To this
Grignard reagent was added dropwise a solution of trichlorophosphine (1.24 g 9.00 mmol) in THF (4.50
mL) over 5 min. After the addition was completed, the mixture was stirred at 80 °C for 3 h and then cooled
down to 0 °C. To this solution was added ca. 2 mL of water and the mixture was stirred at 0 °C for 10 min.
4
The mixture was extracted with AcOEt (15 mL x 3), and the organic layer was dried over anhydrous MgSO ,
filtered, and concentrated under reduced pressure. The product was isolated by column chromatography
on silica gel (hexane / AcOEt = 1 / 1) to give a bis(biphenyl)phosphine oxide (1, 1.96 g, 48% yield).
Bis(biphenyl)phosphine Oxide 1: 48%, white solid, purification: silica gel column chromatography
1
(
hexane / AcOEt = 1 / 1), TLC (hexane / AcOEt = 1 / 2): R
f
= 0.32, H NMR (400 MHz, CDCl
3
)  6.77 (t, J
=
7.6 Hz, 2H), 6.98 (s, 2H), 7.05 (t, J = 6.0 Hz, 2H), 7.17 (t, J = 7.6, 2H), 7.33-7.43 (m, 10H), 7.54 (d, J =
1
3
1
3.6 Hz, 1H), 7.59 (d, J = 13.2 Hz, 1H), 7.61 (d, J = 351.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H); C NMR (100
MHz, CDCl )  126.2, 126.3, 126.6, 126.7, 127.4, 127.5, 127.6, 128.0 (d, J = 9.1 Hz), 128.3, 130.2, 131.6,
32.4, 132.5, 132.8, 136.0 (d, J = 5.5 Hz), 145.6 (d, J = 9.1 Hz); P NMR (162 MHz, CDCl
3
3
1
1
3
)  14.3; IR
-
1
(
(
neat / cm ) 3051, 1543, 1265, 1180, 1130, 1080, 937, 899, 860, 822, 760, 671, 621, 478, 432, 409; HRMS
+
+
EI ) Calcd for C32H23OP (M ) 454.1486, Found 454.1469.
Typical Procedure for the Synthesis of Phosphafluorene Oxide 2: A solution of bis(biphenyl)phosphine
oxide (1, 1.11 g, 2.45 mmol) and Pd(OAc) (27.5 mg, 0.120 mmol) in THF (2.45 mL) was stirred at 50 °C
2
for 6 h. The mixture was cooled to room temperature, and concentrated under reduced pressure. The
product was isolated by column chromatography on silica gel (hexane / AcOEt = 1 / 1) to give a
phosphafluorene oxide (2, 0.83 g, 75% yield).
Phosphafluorene Oxide 2: 75%, white solid, purification: silica gel column chromatography (hexane /
1
AcOEt = 1 / 1), TLC (hexane / AcOEt = 1 / 2): R
f
= 0.36, H NMR (400 MHz, CDCl
3
)  6.37 (d, J = 8.4 Hz,
1
H), 6.56 (s, 1H), 6.64-6.98 (m, 1H), 7.05-7.06 (m, 1H), 7.11-7.25 (m, 3H), 7.28-7.35 (m, 2H), 7.38 (dd, J
=
8.0, 8.0 Hz, 1H), 7.45-7.65 (m, 7H), 7.70 (dd, J = 7.2, 7.2 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 8.04 (d, J =

HETEROCYCLES, Vol. 85, No. 12, 2012
3033
1
3
1
0.4 Hz, 1H), 8.76-8.86 (m, 1H); C NMR (100 MHz, CDCl
Hz), 125.4, 125.5, 126.1, 126.4 (d, J = 105.5 Hz), 126.6, 126.7, 127.5, 127.9 (d, J = 96.4 Hz), 128.1, 128.6
d, J = 103.6 Hz), 128.8 (d, J = 10.9 Hz), 128.9, 129.2 (d, J = 9.1 Hz), 130.8 (d, J = 10.9 Hz), 130.9, 131.0,
3
) δ 119.6 (d, J = 9.1 Hz), 121.2 (d, J = 10.9
(
1
1
31.7, 131.88, 131.94, 132.8, 133.2 (d, J = 12.7 Hz), 134.6, 134.7, 135.5, 136.2 (d, J = 3.6 Hz), 137.0, 137.2,
31
-1
42.0, 142.2, 145.8 (d, J = 10.9 Hz); P NMR (162 MHz, CDCl
3
) δ 31.3; IR (neat / cm ) 3050, 3001, 1188,
1134, 1080, 909, 891, 867, 818, 783, 758, 750, 729, 684, 605, 573, 556, 538, 529, 502, 484, 475, 436, 421;
+
+
HRMS (EI ) Calcd for C H OP (M ) 452.1330, Found 452.1319.
3
2
21
Typical Procedure for the Synthesis of Phosphafluorene 3: To a solution of phosphafluorene oxide (2,
.264 g, 0.580 mmol) and N,N-dimethylaniline (0.703 g, 5.8 mmol) in toluene (5.8 mL) was added
trichlorosilane (0.785 g, 5.8 mmol) dropwise at room temperature, and the mixture was stirred at 80 °C for
6 h. After the mixture was cooled to 0 °C, deoxygenated 1 M aq.NaOH (5.8 mL) was slowly added, and
0
1
the mixture was warmed to room temperature, and then stirred at 50 °C for 0.5 h. The mixture was cooled
to room temperature, and filtered through a pad of celite eluted with deoxygenate ethyl acetate. The
4
organic layer was separated, dried over MgSO , filtered, and concentrated on a rotary evaporator. The
product was isolated by column chromatography on silica gel (hexane / AcOEt = 50 / 1) to give a
phosphafluorene (3, 0.235 g, 93% yield).
Phosphafluorene 3: 93%, white solid, purification: silica gel column chromatography (hexane / AcOEt =
1
5
0 / 1), TLC (hexane / AcOEt = 10 / 1): R
f
= 0.50, H NMR (400 MHz, CDCl
3
) δ 6.80-6.86 (m, 1H), 7.05
(
dd, J = 7.2, 7.2 Hz, 1H), 7.28-7.34 (m, 2H), 7.41-7.49 (m, 4H), 7.55-7.59 (m, 3H), 7.68 (d, J = 8.0 Hz, 1H),
1
3
7
1
1
3
.81 (d, J = 8.4 Hz, 1H), 7.85-8.05 (m, 7H), 8.26 (s, 1H); C NMR (100 MHz, CDCl ) δ 119.6, 121.8, 125.8,
26.28 (d, J = 18.2 Hz), 126.34, 127.5, 127.7, 127.8, 127.9, 128.2, 128.7, 128.9, 129.1 (d, J = 21.8 Hz),
29.50, 129.54, 130.57, 130.63, 130.8 (d, J = 7.2 Hz), 131.0, 132.2, 132.9, 133.0, 133.2, 133.5, 135.6 (d, J
=
23.6 Hz), 139.3 (d, J = 5.4 Hz), 141.1, 141.4, 143.3 (d, J = 18.2 Hz), 143.4 (d, J = 20.0 Hz), 148.2, 148.5;
3
1
-1
P NMR (162 MHz, CDCl
3
) δ -20.2; IR (neat / cm ) 3044, 2965, 1265, 1128, 1020, 939, 872, 864, 818,
+
+
7
4
70, 758, 743, 733, 683, 563, 525, 478, 469, 446; HRMS (EI ) Calcd for C32H21P (M ) 436.1381, Found
36.1359; specific rotation values: (S)-3, [α] -19.0 and (R)-3, [α] +19.0.
D
D
ACKNOWLEDGEMENTS
This work was partially supported by the Ministry of Education, Culture, Sports, Science, and Technology
of Japan.
REFERENCES AND NOTES
1
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