Synthesis of pyridyl-dihydrobenzooxaphosphole ligands and their application in asymmetric hydrogenation of unfunctionalized alkenes

Article abstract of DOI:10.1021/jo4024864

Synthesis of the electron-rich 2-substituted-6-(phenylsulfonyl)pyridines is presented. A series of air-stable, tunable, P-chiral pyridyl- dihydrobenzooxaphosphole ligands were designed and synthesized by a diastereoselective S_NAr substitution of the corresponding sulfonyl pyridines. The ligands were successfully applied in the Ir-catalyzed asymmetric hydrogenation of unfunctionalized alkenes with good enantioselectivities.

Full text of DOI:10.1021/jo4024864

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Article
Synthesis of Pyridyl-dihydrobenzooxaphosphole Ligands and Their
Application in Asymmetric Hydrogenation of Unfunctionalized Alkenes
Bo Qu, Lalith P. Samankumara, Jolaine Savoie, Daniel R Fandrick, Nizar Haddad, Xudong Wei, Shengli Ma,
Heewon Lee, Sonia Rodriguez, Carl A. Busacca, Nathan K. Yee, Jinhua J. Song, and Chris H. Senanayake
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4024864 • Publication Date (Web): 10 Jan 2014
Downloaded from http://pubs.acs.org on January 14, 2014
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Synthesis of Pyridyl-dihydrobenzooxaphosphole Ligands and Their Application in Asymmetric
Hydrogenation of Unfunctionalized Alkenes
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Bo Qu,* Lalith P. Samankumara, Jolaine Savoie, Daniel R. Fandrick, Nizar Haddad, Xudong Wei, Shengli Ma,
Heewon Lee, Sonia Rodriguez, Carl A. Busacca, Nathan K. Yee, Jinhua J. Song, Chris H. Senanayake
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Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA
bo.qu@boehringer-ingelheim.com
Table of Contents Graphic
Abstract
Synthesis of the electron rich 2-substituted-6-(phenylsulfonyl)pyridines is presented. A series of
air-stable, tunable, P-chiral pyridyl-dihydrobenzooxaphosphole ligands were designed and synthesized by
a diastereoselective S Ar substitution of the corresponding sulfonyl pyridines. The ligands were
N
successfully applied in the Ir-catalyzed asymmetric hydrogenation of unfunctionalized alkenes with good
enantioselectivities.
Introduction
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Chiral phosphine ligands have played a central role in the field of asymmetric catalysis toward
the rapid synthesis of enantiomerically pure pharmaceuticals and fine chemicals.1 Development of
structurally novel, sterically or electronically tunable, and operationally convenient chiral phosphorus
ligands continues to be of great interest in further broadening the scope of asymmetric hydrogenation as
well as in the discovery of new efficient transition metal catalyzed asymmetric reactions.2 Even though an
impressive number of chiral phosphine ligands have been developed since the pioneering work of Kagan,
Noyori, Knowles, and others,3 only a limited set of these has been applied in large scale chemical
processes presumably due to their lengthy synthesis as well as the challenges associated with the fine
tuning of the electronic and steric properties.4
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Recently we have developed a rigid modular P-chiral dihydrobenzooxaphosphole core structure 1
(Scheme 1). A series of ligands such as BIBOP and POP were derived from this chiral intermediate to
enable high enantioselectivities in the rhodium catalyzed asymmetric hydrogenation of functionalized
alkenes, such as enamides and unsaturated aminoacid derivatives.5 BI-DIME has been demonstrated as a
highly efficient ligand for the palladium catalyzed Suzuki-Miyuara and Buchwald-Hartwig couplings of
sterically demanding substrates.6 Herein, we report the synthesis of a new series of air-stable chiral
pyridyl-phosphine ligands (BoQPhos) and the application of these ligands in the iridium catalyzed
asymmetric hydrogenation of unfunctionalized tri- and tetrasubstituted alkenes.
Scheme 1. Chiral ligands developed from the P-chiral dihydrobenzooxaphosphole 1
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Despite the success of many chiral ligands applied for rhodium- and ruthenium-catalyzed
hydrogenations particularly for alkenes bearing a coordinating group next to the C=C bond,7
unfunctionalized alkenes have remained a challenging class of substrates, as there are no functional
groups in position to guide the catalyst in differentiating between the enantiofaces of the alkenes.8 Pfaltz
and others have shown that P,N ligands such as phosphinooxazoline ligands (PHOX) are particularly
effective for the Ir-catalyzed asymmetric hydrogenation of unfunctionalized alkenes and furnishing high
enantioselectivities.9 Inspired by these results, we aimed to develop a new class of pyridyl-phosphine P,N
ligands based on the dihydrobenzooxaphosphole core 1. The notable features of these new P,N ligands are
their tunability by variation of the substitution on both the phenyl and pyridyl rings. We anticipated that
the steric and electronic variation of the substituents would have a great impact on the efficiency of their
iridium complexes when applied to the asymmetric hydrogenation of unfunctionalized alkenes.
Results and Discussions
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To construct the pyridyl-phosphines in a concise manner, SNAr coupling of 2-sulfonylpyridines
with the derivatives of 1 was explored due to the necessary acidity of the α-proton to the phosphorous
atom in the dihydrobenzooxaphosphole core. The sulfonylpyridines are valuable building blocks, which
can be easily displaced under nucleophilic substitution conditions to incorporate pyridine moieties into
complex molecules.10 Unsubstituted sulfonylated pyridine 3a was readily obtained from a direct SNAr
displacement of 2-chloropyridine with benzene sulfinic acid sodium salt in 80% yield in the presence of
acetic acid (Scheme 2, Method a). However, no product formation was observed with 2-chloro-6-
phenylpyridine or electron rich 2-chloro-6-alkoxypyridines. Aryl sulfones are generally prepared by
oxidation of the sulfides,11 metal-catalyzed cross coupling of aryl halides with arenesulfinic acid salts,12 or
the corresponding electrophilic aromatic substitution reactions.13 Most of these methods are only
applicable to the electron deficient aryl halides. Indeed, an alternative approach applying Cu(I) catalyzed
coupling of 2-bromo-6-methoxypyridine with phenyl sulfinic acid salts provided a low yield for 3b (<
20%). Gratifyingly, 3b was obtained in 90% yield from SNAr displacement of the 2,6-disulfonylated
pyridine 2 (Method b). Even though not previously reported, pyridine disulfone 2 was readily synthesized
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in 89% yield by treatment of the 2,6-dichloropyridine with phenyl sulfinic acid salt at 100 °C in DMAc.13
Similarly, 2-phenyl-6-(phenylsulfonyl)pyridine 3c was obtained in 80% yield from the reaction with
PhMgBr. 2-ethoxy-6-(phenylsulfonyl)pyridine 3d and 2-phenoxy-6-(phenylsulfonyl)pyridine 3e were
also isolated in high yields, 91% and 88% respectively, by treatment with the corresponding alcohols in
the presence of KHMDS. Electron rich 2-substituted 6-(phenylsulfonyl)pyridines could be readily
prepared through Method b.
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Scheme 2. Synthesis of phenylsulfonylpyridines
With sulfonylated pyridines in hand, SNAr reaction of 2-(phenylsulfonyl)pyridine with chiral
precursor 1a was first evaluated. Subjecting the mixture to one equivalent of LDA at -78 °C provided
only a 35% conversion. However, complete conversion was obtained by increasing the LDA
stoichiometry to 3 equiv (Scheme 3). Two diastereomers were observed from the coupling. The cis-
diastereomer was the initial major isomer right after MeOH quench at -78 °C. After warming up to rt, the
cis-isomer gradually converted to the thermodynamically more stable trans-isomer with the bulky tert-
butyl group positioned trans to the pyridyl functionality. High trans:cis ratio of >99:1 could be obtained
after treating with additional aqueous NaOH. The trace amount of the cis-diastereomer was removed
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easily by silica gel pur
ification or by recrystalli
zation. Pure 4a was isol
ated in 85% yield. The absolute
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configuration of the trans-isomer was confirmed by the X-ray single crystal structure of phosphine oxide
4a.14 Reduction of the P,N oxide 4a with polymethylhydrosiloxane (PMHS) and Ti(OiPr)4 conditions
provided phosphine ligand 5a as a white solid in 86% yield.
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Scheme 3. Mechanism of the trans-diastereomer formation
Li
H
O
H
O
O
P
O
O
P
O
P
MeOH
quench
OH-
rt
PhO2S
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N
P O
N
N
-78 oC
O
LDA (3 equiv)
-78 oC
OMe
OMe
OMe
OMe
cis
trans
4a
1a
THF
>99:1
Figure 1. X-ray single crystal structure of 4a, ellipsoids at 50% probability
Under the same reaction conditions, a series of pyridyl-dihydrobenzooxaphosphole ligands 5b-f
were synthesized in good yields starting from 1 in two steps (Scheme 4). Both the SNAr coupling and the
reduction reactions are stereoselective. Phosphine oxides and free phosphines are all >99% ee.20 The
isolated free phosphines proved to be air-stable. Compound 5a was exposed to air at ambient temperature
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for one month with no detectable amount of oxidation product as determined by P NMR analysis. The
corresponding cationic iridium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BArF) complexes were
then prepared according to known procedures and purified by silica gel chromatography.15 The iridium
complexes of 6a-d from the unsubstituted pyridyl phosphine ligands were obtained as red-orange solids.
However, the iridium complexes 6e and 6f from the ortho-substituted pyridyl phosphine ligands were
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obtained as light yellow solids. More importantly, the H NMR spectroscopy of catalyst 6e from the bis-
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methoxy ligand 5e showed only one methoxy signal at 3.96 ppm. The detailed NMR analyses indicated
that complex 6e is a five-membered chelate hydridoiridium derivative resulted by an intramolecular C-H
activation of the methoxy group on pyridine.21 The cyclometalated methylene group was identified by two
unequal 1H signals at 6.72 and 7.32 ppm and one methylene group 13C NMR signal at 61.62 ppm from the
DEPT 13C NMR spectroscopy. Additionally a metal hydride was located at -13.34 ppm as a doublet from
coupling with the phosphorous atom. Similarly, hydridoiridium complex 6f was formed by C-H bond
oxidative addition of the phenyl substituent which is in close proximity to the metal center. The resulting
hydridoiridium complexes 6e and 6f are stable in solution for at least one week (CDCl3, 293 k).
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Scheme 4. Synthesis of the iridium pyridyl-dihydrobenzooxaphosphole complexes
Table 1. Asymmetric hydrogenation of dimethylindene 7a
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Entry Catalyst
Conv%
100%
40%
er of 8a
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6b
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72:28
88:12
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90%
6%
15%
10%
With the new pyridyl-phosphorous iridium complexes in hand, asymmetric hydrogenation of
tetrasubstituted 2,3-dimethylindene 7a was examined using the complexes 6a-f as catalysts (Table 1).
Screening of solvents has identified methylene chloride as the best hydrogenation solvent. Complete
conversion and good enantioselectivity of 86:14 er were obtained at 400 psi H2 and 23 °C with Ir-
complex 6a derived from the unsubstituted pyridyl ligand 5a (Table 1, entry 1). However the
hydridoiridium complexes 6e and 6f impeded both the reactivity and the selectivity (entries 5 and 6). Aryl
groups were also incorporated at the 4-position of the compound 1; low reactivity and selectivity were
observed with 4-phenyl substituted catalyst 6b (entry 2) and 9-anthracenyl substituted 6d (entry 4). To
our delight, the catalyst 6c obtained from incorporation of the 2,6-dimethoxyphenyl functionality
produced 8a with the optimal results of up to 88:12 er (entry 3).
Scheme 5. Asymmetric hydrogenation of alkenes with catalyst 6c
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Catalyst 6c was further evaluated on asymmetric hydrogenation of additional tri- and
tetrasubstituted alkenes (Scheme 5). Treatment of trans-α-methylstilbene 7b in the presence of complex
6c produced the adduct 8b in a 95:5 er. Reduction of phenyldihydronaphthalene 7c with catalyst 6c
generated the adduct 8c in an 88:12 er. Dihydronaphthalene 7d is generally more difficult to hydrogenate
enantioselectively; a good enantiomeric ratio of 90:10 was obtained for 8d with an 80% conversion at 400
psi H2 in the presence of catalyst 6c. In comparison, the optimized PHOX ligand produced 8d in an 89:11
er and 46% conversion.16 Recently we have reported a higher er of 95:5 for 8d using the phosphine
imidazoline based iridium BIPI 238 complex.17 Reduction of (E)-2-methyl-3-phenylpropenol (7e)
containing an allylic hydroxyl group with catalyst 6c provided the adduct 8e in a 93:7 er and complete
conversion.
Conclusions
A new method for the synthesis of electron rich 2-substituted 6-(phenylsulfonyl)pyridines was
reported starting from 2,6-disulfonylated pyridine. A series of new air stable chiral pyridyl-
dihydrobenzooxaphosphole ligands (BoQPhos) were conveniently synthesized by diastereoselective SNAr
displacement of the key intermediate 1 with the sulfonylated pyridine derivatives. Initial application of
these ligands to the asymmetric hydrogenation of challenging unfunctionalized alkenes yielded good
enantioselectivities. The electronic and steric properties of the ligand system can be readily tuned by the
judicious choice of substitutions on the chiral core structure and on the pyridine ring thereby providing a
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facile approach to the ligand optimization toward a diverse number of transition metal catalyzed
asymmetric transformations.
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Experimental Section
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General Methods. All starting materials and reagents were purchased from the commercial sources and
used without further purification. All 1H and 13C NMR data were referenced to the internal deuterated
solvent relative to TMS at 0 ppm. High resolution mass spectroscopy was performed on a TOF instrument
with ESI and positive and negative ionization modes. Flash chromatography was performed on an
automated system with silica columns. Compounds 1a,5a 1b,5a 1c,6a and 1d18 have been previously
described. Sulfonyl pyridines 3a11and 3c19 are known compounds, alternative syntheses are described
herein.
Synthesis of the sulfonyl pyridines
2,6-Bis(phenylsulfonyl)pyridine (2). To a N2 purged reactor was charged 10.0 g (67.57 mmol) of 2,6‐
dichloropyridine, 16.64 g (101.4 mmol) of sodium benzenesulfinate, 5.6 g (20.73 mmol) of
tetrabutylammonium chloride and 100 mL of N,N‐dimethylacetamide. The mixture was heated to 100 °C
and stir for 4 h. Then another portion of 16.64 g (101.4 mmol) sodium benzenesulfinate was charged and
stir at 100 °C for 14 h until more than 95% conversion was obtained. The mixture was cooled down to rt
and 300 mL of water was added to observe formation of white precipitates. The slurry was stirred at rt for
1 h. The solid was filtered and washed with 20 ml of isopropanol. 21.6 g of 2 was obtained as a white
solid after drying under vacuum at 50 °C, 89% yield; mp 178.1-180.4 °C. 1H NMR (400 MHz, CDCl3) δ
8.31 (d, J = 7.6 Hz, 2H), 8.18-8.16 (m, 1H), 7.94-7.91 (m, 4H), 7.66 (tt, J = 7.5, 1.2 Hz, 2H), 7.51 (t, J =
7.8 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 159.5, 140.6, 137.4, 134.2, 129.4, 129.1, 124.2; HRMS (ESI)
m/z 360.0358 (M + H+), calc. for C17H14NO4S2 360.0359.
2-(Phenylsulfonyl)pyridine (3a). A 500 mL reactor was charged 113.6 g (1.0 mol) 2-chloropyridine, first
portion of PhSO2Na (82 g, 0.5 mol, 0.5 equiv), 226 ml acetic acid and 72 mL water. The mixture was
heated to 90 °C and stirred for 2 h. Then 0.75 equiv of PhSO2Na was added in three portions (41 g, 0.25
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equiv each) in 15 h. HPLC analysis showed >97% conversion. The mixture was cooled down to rt and
150 mL water was added. Stirring was continued for 30 min. The slurry was filtered and the crude solid
was recharged to a reactor and 250 mL of isopropanol was added. The slurry was stirred at 60 °C for 30
min and then cooled down to rt. The resulted white solid was filtered and dried in the oven to give 175 g
of 3a in 80% yield. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 4.8 Hz, 1H), 8.21 (d, J = 7.9 Hz, 1H), 8.08
(m, 2H), 7.95 (dt, J = 7.8, 1.7 Hz, 1H), 7.60 (m, 1H), 7.55 (m, 2H), 7.48 (ddd, J = 7.6, 4.7, 1.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 158.8, 150.5, 138.9, 138.1, 133.8, 129.1, 128.9, 126.9, 122.2.
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2-Methoxy-6-(phenylsulfonyl)pyridine (3b). To a N2 purged reactor was charged 5.0 g (13.9 mmol) of
2a and 50 mL of anhydrous THF to result a slurry. MeONa (25 wt% in MeOH) (1.1 equiv) was added
drop wise to the stirring reaction mixture. The resulting slurry was stirred for 1 h at room temperature. A
complete conversion was observed by LC-MS. The slurry was filtered and washed with IPA; dried in
oven overnight at 50 °C to give 1.94 g 3b as a white solid. The mother liquor was concentrated and 15
mL of IPA was added and warmed until complete dissolution. The mixture was cooled down to 10 °C and
held for 1 h. The second crop of solid was filtered and dried to yield another 1.17 g of white solid, total 90%
yield; mp 74.6-75.8 °C. 1H NMR (400 MHz, CDCl3) δ 8.12-8.09 (m, 2H), 7.78-7.73 (m, 2H), 7.64 (tt, J =
7.4, 1.3 Hz, 1H), 7.58-7.53 (m, 2H), 6.88 (dd, J = 7.7, 1.4 Hz, 1H), 3.87 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.0, 155.7, 139.7, 138.9, 133.6, 129.1, 128.9, 115.5, 114.9, 54.0; HRMS (ESI) m/z 250.0528
(M + H+), calc. for C12H12NO3S 250.0532.
2-Phenyl-6-(phenylsulfonyl)pyridine (3c). To a stirring solution of bis-(phenylsulfonyl)pyridine 2a (1.0
g, 2.78 mmol) in 10 mL THF at room temperature was charged 1.0 M PhMgBr (5.56 ml, 2.0 equiv)
slowly over a period of 10 min. The progress of the reaction was monitored by LC-MS. Upon complete
consumption of the starting material after 2 h, the mixture was quenched with MeOH (2 mL). The crude
mixture was then evaporated to dryness and 3c was isolated by flash column chromatography (silica gel,
15% ethyl acetate in hexanes) to yield 656 mg white solid after dryness, 80% yield. 1H NMR (400 MHz,
CDCl3) δ 8.14-8.08 (m, 3H), 7.95-7.91 (m, 3H), 7.83-7.86 (m, 1H), 7.62-7.51 (m, 3H), 7.46-7.40 (m, 3H);
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13C NMR (100 MHz, CDCl3) δ 158.7, 158.0, 138.9, 138.7, 137.1, 133.7, 130.0, 129.2, 128.9, 128.8, 127.0,
123.1, 119.8.
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2-Ethoxy-6-(phenylsulfonyl)pyridine (3d). To a N2 purged reactor was charged 1.08 g (3.0 mmol) of
2,6‐bis(phenylsulfonyl)pyridine 2, 7 mL of anhydrous THF and 0.18 mL of EtOH (3.06 mmol, 1.02
equiv). 3.0 mL of 1.0 M KHMDS in THF (3.0 mmol, 1.0 equiv) was added drop wise to the stirring
reaction at rt. The resulting mixture was stirred for 1 h at rt. A complete conversion was observed by LC-
MS. Upon completion, 5 mL water was added. The mixture was then concentrated and 10 mL EtOAc was
added. The layers were separated and the aqueous layer was further extracted. The combined organic
layer was dried and purified on silica to yield 723 mg of 3d as a white solid after dryness, 91% yield; mp
95.1-96.1 °C. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.6 Hz, 2H), 7.74 (m, 2H), 7.61 (t, J = 7.5 Hz,
1H), 7.55 (t, J = 7.7 Hz, 2H), 6.84 (dd, J = 7.3, 1.7 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 163.7, 155.6, 139.7, 139.0, 133.5, 129.0, 128.8, 115.6, 114.6, 62.6,
14.1; HRMS (ESI) m/z 264.0684 (M + H+), calc. for C13H14NO3S 264.0694.
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2-Phenoxy-6-(phenylsulfonyl)pyridine (3e). Same procedures as above with 288 mg of phenol (3.06
mmol, 1.02 equiv). 820 mg of 3e was isolated as a white solid, 88% yield; mp 108.1-109.6 °C. 1H NMR
(400 MHz, CDCl3) δ 7.88-7.83 (m, 4H), 7.58 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 7.9
Hz, 2H), 7.26 (m, 1H), 7.05 (m, 1H), 6.99 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 163.3,
156.3, 152.9, 140.8, 138.3, 133.5, 129.5, 129.3, 128.7, 125.2, 121.5, 115.7, 115.3; HRMS (ESI) m/z (M +
H+) 312.0678, calc. for C17H14NO3S 312.0689.
Synthesis of the phosphine oxides
(2R,3S)-3-(tert-butyl)-4-methoxy-2-(pyridin-2-yl)-2H-benzo[d][1,3]oxaphosphole 3-oxide (4a).
Intermediate 1a (1.0 g, 4.163 mmol) and pyridine sulfone 3a (0.913 g, 4.163 mmol) were dissolved in 10
ml of anhydrous THF under argon. The mixture was cooled to -78 °C with a dry ice/acetone bath. To the
stirred solution 2.64 mL (12.5 mmol) of LDA (2.0 M in THF/ethylbenzene) was added drop wise. The
internal temperature was maintained under -70 °C for an additional hour. Upon completion, the reaction
was quenched with MeOH at -78 °C. The mixture was warmed to rt and stirring continued for 2 h. The
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reaction mixture should be basic at PH ≥ 12. Aqueous NaOH (30 wt%) was added if necessary. The
mixture was then concentrated to dryness. The organic layer was extracted with CH2Cl2 and dried with
anhydrous Na2SO4 and compound 4a was purified on silica with 5% MeOH in CH2Cl2 to yield 1.2 g of
white solid after dryness, 91% yield; mp 186.1-188.5 °C. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 4.7
Hz, 1H), 7.68 (dt, J = 7.7, 1.7 Hz, 1H), 7.45 (t, J = 8.3 Hz, 1H), 7.40 (dd, J = 8.0, 0.5 Hz, 1H), 7.21 (t, J =
6.2 Hz, 1H), 6.68 (dd, J = 8.3, 3.0 Hz, 1H), 6.53 (dd, J = 8.3, 4.2 Hz, 1H), 5.67 (d, JH-P = 2.9 Hz, 1H),
3.88 (s, 3H), 1.39 (d, JH-P = 16.6 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 165.6 (d, JC-P = 15.0 Hz), 161.5
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(d, JC-P = 1.9 Hz), 154.4 (d, JC-P = 3.4 Hz), 149.2, 136.7, 136.6, 123.0 (d, JC-P = 1.8 Hz), 122.3 (d, JC-P
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2.2 Hz), 106.1 (d, JC-P = 5.1 Hz), 103.6 (d, JC-P = 5.5 Hz), 103.2 (d, JC-P = 89.2 Hz), 79.1 (d, JC-P = 53.9
Hz), 55.6, 34.3 (d, JC-P = 73.9 Hz), 25.0; 31P NMR (160 MHz, CDCl3) δ 61.65; HRMS (ESI) m/z
318.1237 (M + H+), calc. for C17H21NO3P 318.1254.
(2R,3S)-3-(tert-butyl)-4-phenyl-2-(pyridin-2-yl)-2H-benzo[d][1,3]oxaphosphole 3-oxide (4b). 1.09 g
of white solid was isolated after purification with 0-2% MeOH in CH2Cl2, 72% yield; mp 99.2-101.6 °C.
1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 5.0 Hz, 1H), 7.76-7.73 (m, 3H), 7.57 (dt, J = 7.9, 0.9 Hz, 1H),
7.48 (dd, J = 8.0, 0.9 Hz, 1H), 7.18-7.34 (m, 3H), 7.26-7.22 (m, 1H), 7.13-7.07 (m, 2H), 5.71 (d, J =1.0
Hz, 1H), 0.91 (d, JH-P = 16.5 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 164.6 (d, JC-P = 17.6 Hz), 154.8 (d,
JC-P = 3.7 Hz), 149.3 (d, JC-P = 1.2 Hz), 147.0 (d, JC-P = 5.6 Hz), 140.6 (d, JC-P = 1.8 Hz), 136.7 (d, JC-P
=
1.8 Hz), 134.9 (d, JC-P = 1.9 Hz), 129.9, 128.5, 128.4, 123.9 (d, JC-P = 7.8 Hz), 122.9 (d, JC-P = 1.8 Hz),
121.6 (d, JC-P = 2.2 Hz), 112.8 (d, JC-P = 85.9 Hz), 112.4 (d, JC-P = 5.3 Hz), 77.8 (d, JC-P = 55.6 Hz), 34.6
(d, JC-P = 71.3 Hz), 24.4; 31P NMR (160 MHz, CDCl3) δ 62.19; HRMS (ESI) m/z 364.1459 (M + H+), calc.
for C22H23NO2P 364.1461.
(2R,3S)-3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2-(pyridin-2-yl)-2H-benzo[d][1,3]oxaphosphole 3-
oxide (4c). 1.37 g white solid was obtained after purification with 100% EtOAc, 78% yield; mp 186.0-
188.4 °C. 1H NMR (500 MHz, CDCl3) δ 8.57 (d, J = 4.7 Hz, 1H), 7.68 (dt, J = 7.8, 1.6 Hz, 1H), 7.56 (t, J
= 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.27 (t, J = 8.3 Hz, 1H), 7.21 (t, J = 6.2 Hz, 1H), 7.05 (dd, J = 8.2,
3.2 Hz, 1H), 6.98 (dd, J = 7.4, 3.2 Hz, 1H), 6.58 (dd, J = 8.2, 5.0 Hz, 2H), 5.60 (d, J = 1.6 Hz, 1H), 3.74
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(s, 3H), 3.58 (s, 3H), 0.95 (d, JH-P = 16.2 Hz, 9H); 13C NMR (125 MHz, CDCl3) δ 164.2 (d, JC-P = 17.7
Hz), 158.8, 157.3, 154.9 (d, JC-P = 3.1 Hz), 149.1 (d, JC-P = 0.9 Hz), 138.8 (d, JC-P = 5.3 Hz), 136.4, 134.3,
129.9, 125.6 (d, JC-P = 8.4 Hz), 122.9 (d, JC-P = 1.4 Hz), 122.4 (d, JC-P = 2.3 Hz), 117.4 (d, JC-P = 2.0 Hz),
114.7 (d, JC-P = 89.5 Hz), 112.3 (d, JC-P = 5.4 Hz), 104.6, 103.0, 78.2 (d, JC-P = 55.3 Hz), 56.1, 55.4, 34.2
(d, JC-P = 71.8 Hz), 23.9 (d, JC-P = 0.7 Hz); 31P NMR (200 MHz, CDCl3) δ 60.11; HRMS (ESI) m/z
424.1654 (M + H+), calc. for C24H27NO4P 424.1672.
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(2R,3S)-4-(anthracen-9-yl)-3-(tert-butyl)-2-(pyridin-2-yl)-2H-benzo[d][1,3]oxaphosphole 3-oxide
(4d). 1.73 g white solid was obtained after purification with 0-2% MeOH in CH2Cl2, 90% yield; mp 243-
246 °C (decomp). 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 5.0 Hz, 1H), 8.51 (s, 1H), 8.05 (d, J = 8.4
Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.76-7.69 (m, 3H), 7.62 (t, J = 8.6 Hz, 2H), 7.47-7.36 (m, 4H), 7.30 (dd,
J = 8.4, 2.6 Hz, 1H), 7.22 (d, J = 6.0 Hz, 1H), 7.16 (dd, J = 7.2, 3.2 Hz, 1H), 5.60 (d, J = 4.4 Hz, 1H),
0.45 (d, JH-P = 16.5 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 164.9 (d, JC-P = 16.2 Hz), 154.3 (d, JC-P = 3.2
Hz), 148.9, 142.1 (d, JC-P = 5.6 Hz), 136.6 (d, JC-P = 1.4 Hz), 134.5 (d, JC-P = 1.5 Hz), 134.4 (d, JC-P = 1.9
Hz), 131.3, 131.1, 130.3 (d, JC-P = 4.5 Hz), 128.7, 128.4, 127.8. 127.2, 126.5 (d, JC-P = 8.1 Hz), 126.2,
125.9, 125.7, 125.4, 124.8, 123.3 (d, JC-P = 2.2 Hz), 123.1 (d, JC-P = 1.5 Hz), 117.2 (d, JC-P = 85.5 Hz),
113.4 (d, JC-P = 4.9 Hz), 78.9 (d, JC-P = 55.7 Hz), 33.8 (d, JC-P = 71.3 Hz), 24.0; 31P NMR (160 MHz,
CDCl3) δ 58.55; HRMS (ESI) m/z 464.1770 (M + H+), calc. for C30H27NO2P 464.1774.
(2R,3S)-3-(tert-butyl)-4-methoxy-2-(6-methoxypyridin-2-yl)-2H-benzo[d][1,3]oxaphosphole 3-oxide
(4e). 1.18 g white solid was obtained after purification with 80% EtOAc in hexanes, 82% yield; mp
164.9-167.2 °C. 1H NMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.7 Hz, 1H), 7.44 (t, J = 8.2 Hz, 1H), 6.98 (d, J
= 7.4 Hz, 1H), 6.69 (dd, J = 8.4, 2.6 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.51 (dd, J = 8.0, 4.0 Hz, 1H),
5.55 (d, J = 1.8 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 1.41 (d, JH-P = 16.6 Hz, 9H); 13C NMR (100 MHz,
CDCl3) δ 165.6 (d, JC-P = 15.1 Hz), 163.4 (d, JC-P = 1.6 Hz), 161.6 (d, JC-P = 1.9 Hz), 151.8 (d, JC-P = 4.3
Hz), 139.1 (d, JC-P = 1.9 Hz), 136.5, 114.0 (d, JC-P = 3.0 Hz), 110.0 (d, JC-P = 2.2 Hz), 106.1 (d, JC-P = 5.2
Hz), 103.5 (d, JC-P = 5.6 Hz), 102.4 (d, JC-P = 89.2 Hz), 78.6 (d, JC-P = 53.9 Hz), 55.6, 53.4, 34.3 (d, JC-P
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74.3 Hz), 25.1; 31P NMR (160 MHz, CDCl3) δ 61.51; HRMS (ESI) m/z 348.1350 (M + H+), calc. for
C18H23NO4P 348.1359.
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(2R,3S)-3-(tert-butyl)-4-methoxy-2-(6-phenylpyridin-2-yl)-2H-benzo[d][1,3]oxaphosphole 3-oxide
(4f). 1.16 g white solid was obtained after purification with 50% EtOAc in hexanes, 71% yield; mp 172.2-
174.3 °C. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.9 Hz, 2H), 7.75 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 7.9
Hz, 1H), 7.48-7.35 (m, 5H), 6.71 (dd, J = 8.2, 2.9 Hz, 1H), 6.54 (dd, J = 8.1, 4.1 Hz, 1H) 5.77 (d, J = 3.3
Hz, 1H), 3.88 (s, 3H), 1.45 (d, J = 16.5 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 165.7 (d, JC-P = 15.0 Hz),
161.5 (d, JC-P = 1.9 Hz), 156.6 (d, JC-P = 1.2 Hz), 154.2 (d, JC-P = 3.6 Hz), 139.2, 137.5 (d, JC-P = 1.7 Hz),
136.6, 128.9, 128.6, 127.0, 120.6 (d, JC-P = 2.4 Hz), 119.7 (d, JC-P = 1.9 Hz), 106.2 (d, JC-P = 5.1 Hz),
103.5 (d, JC-P = 5.6 Hz), 102.7 (d, JC-P = 89.0 Hz), 79.5 (d, JC-P = 53.2 Hz), 55.6, 34.3 (d, JC-P = 73.8 Hz),
25.2; 31P NMR (160 MHz, CDCl3) δ 61.24; HRMS (ESI) m/z 394.1572 (M + H+), calc. for C23H25NO3P
394.1567.
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General procedure for the reduction of phosphine oxides
2-((2R,3R)-3-(tert-butyl)-4-methoxy-2,3-dihydrobenzo[d][1,3]oxaphosphol-2-yl)pyridine (5a). To a
Schlenk flask under argon was added 4a (500 mg, 1.576 mmol), THF (10 mL), PMHS (1.2 mL) and
Ti(OiPr)4 (0.93 mL, 3.15 mmol). The mixture was stirred at 65 °C for 14 h. Upon complete conversion by
31P NMR analysis, the mixture was concentrated under vacuum. Then the flask was cooled to 0 oC and 20
ml of degassed 30% aqueous NaOH was added slowly with caution. Extreme H2 gas evolution was
observed in the beginning. After complete addition the mixture was heated to 65 ºC and stirred for 1 h.
The mixture was cooled down to rt and the product was extracted with degassed MTBE (3 x 30 mL)
under argon. The combined organic layer was filtered through a plug of neutral alumina with anhydrous
MgSO4 on the top. 410 mg of 5a was obtained as a white solid after dryness, 86% yield. 1H NMR (400
MHz, CDCl3) δ 8.55 (d, J = 4.7 Hz, 1H), 7.51 (td, J = 7.7, 1.6 Hz, 1H), 7.28 (t, J = 8.1 Hz, 1H), 7.10 (d, J
= 7.8 Hz, 1H), 7.06 (t, J = 6.2 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.47 (dd, J = 8.1, 3.6 Hz, 1H), 6.02 (s,
1H), 3.78 (s, 3H), 1.11 (d, JH-P = 12.4 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 165.6 (d, JC-P = 15.2 Hz),
161.5 (d, JC-P = 1.8 Hz), 154.4 (d, JC-P = 3.6 Hz), 149.2 (d, JC-P = 0.8 Hz), 136.7, 136.6, 123.0 (d, JC-P
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1.7 Hz), 122.2 (d, JC-P = 2.4 Hz), 106.1 (d, JC-P = 5.2 Hz), 103.6 (d, JC-P = 5.6 Hz), 103.2 (d, JC-P = 89.2
Hz), 79.1 (d, JC-P = 53.8 Hz), 55.6, 34.2 (d, JC-P = 73.7 Hz), 25.0; 31P NMR (160 MHz, CDCl3) δ 12.85;
HRMS (ESI) m/z 302.1319 (M + H+), calc. for C17H21NO2P 302.1304.
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2-((2R,3R)-3-(tert-butyl)-4-phenyl-2,3-dihydrobenzo[d][1,3]oxaphosphol-2-yl)pyridine (5b). 383 mg
white solid, 70% yield. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J = 4.5 Hz, 1H), 7.59-7.62 (m, 3H), 7.42 (t,
J = 7.8 Hz, 1H), 7.25-7.35 (m, 4H), 7.14 (t, J = 6.7 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.05 (dd, J = 7.4 Hz,
3.4 Hz, 1H), 6.03 (s, 1H), 0.79 (d, J = 12.2 Hz, 9H); 13C NMR (125 MHz, CDCl3) δ 164.4, 161.3 (d, JC-P
= 14.3 Hz), 149.6 (d, JC-P = 1.7 Hz), 146.5 (d, JC-P = 12.9 Hz), 142.1, 136.7 (d, JC-P = 1.2 Hz), 131.6,
129.3, 129.1, 128.4, 127.4, 122.6 (d, JC-P = 2.8 Hz), 121.9 (d, JC-P = 2.5 Hz), 120.6 (d, JC-P = 22.3 Hz),
119.2 (d, JC-P = 3.5 Hz), 109.9, 85.3 (d, JC-P = 27.4 Hz), 32.8 (d, JC-P = 22.6 Hz), 26.8 (d, JC-P = 13.8 Hz);
31P NMR (200 MHz, CDCl3) δ 15.38; HRMS (ESI) m/z 348.1512 (M + H+), calc. for C22H23NOP
348.1512.
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2-((2R,3R)-3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphol-2-
yl)pyridine (5c). 407 mg white solid, 75% yield. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 4.7 Hz, 1H),
7.58 (dt, J = 8.0, 1.5 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.26-7.21 (m, 2H), 7.12 (t, J = 6.0 Hz, 1H), 7.05 (d,
J = 8.0 Hz, 1H), 6.93 (dd, J = 7.6, 3.2 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.99 (s,
1H), 3.73 (s, 3H), 3.26 (s, 3H), 0.88 (d, JH-P = 12.2 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 163.6, 161.7
(d, JC-P = 14.2 Hz), 157.6, 156.9, 149.2 (d, JC-P = 1.5 Hz), 139.1 (d, JC-P = 17.0 Hz), 136.5, 130.9, 129.1,
124.4 (d, JC-P = 4.1 Hz), 123.9 (d, JC-P = 17.1 Hz), 121.6 (d, JC-P = 2.4 Hz), 119.5 (d, JC-P = 3.7 Hz), 119.3
(d, JC-P = 21.5 Hz), 109.3, 104.4, 103.5, 86.0 (d, JC-P = 28.1 Hz), 55.43, 55.41, 31.9 (d, JC-P = 21.1 Hz),
26.7 (d, JC-P = 14.7 Hz); 31P NMR (160 MHz, CDCl3) δ 17.71; HRMS (ESI) m/z 408.1700 (M + H+), calc.
for C24H27NO3P 408.1723.
2-((2R,3R)-4-(anthracen-9-yl)-3-(tert-butyl)-2,3-dihydrobenzo[d][1,3]oxaphosphol-2-yl)pyridine (5d).
613 mg white solid, 87% yield. 1H NMR (500 MHz, CDCl3) δ 8.4-8.2 (m, 2H), 7.80-7.76 (m, 3H), 7.48-
6.79 (m, 11H), 5.88 (s, 1H), 0.45 (d, JH-P = 11.5 Hz, 9H); 13C NMR (125 MHz, CDCl3) δ 164.6, 161.2 (d,
JC-P = 14.5 Hz), 149.7, 142.8 (d, JC-P = 16.6 Hz), 136.6, 136.0, 131.5, 131.3, 130.6, 128.9, 128.6, 128.3,
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127.2, 127.0, 126.9, 125.8 (d, JC-P = 3.6 Hz), 125.6, 125.4, 125.3, 124.9, 124.8 (d, JC-P = 21.3 Hz), 121.9
(d, JC-P = 2.0 Hz), 119.3 (d, JC-P = 3.8 Hz), 110.4, 86.2 (d, JC-P = 27.6 Hz), 31.6 (d, JC-P = 22.4 Hz), 27.1 (d,
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C-P = 14.6 Hz); 31P NMR (200 MHz, CDCl3) δ 15.46; HRMS (ESI) m/z 448.1823 (M + H+), calc. for
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C30H27NOP 448.1825.
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2-((2R,3R)-3-(tert-butyl)-4-methoxy-2,3-dihydrobenzo[d][1,3]oxaphosphol-2-yl)-6-methoxypyridine
(5e). Same procedure as above with addition of 2.1 mL of PMHS, 465 mg white solid was obtained in 89%
yield. 1H NMR (500 MHz, CDCl3) δ 7.41 (t, JH-P = 7.8 Hz, 1H), 7.29 (t, JH-P = 8.2 Hz, 1H), 6.74 (d, JH-P
=
7.5 Hz, 1H), 6.70 (d, JH-P = 8.2 Hz, 1H), 6.52 (d, JH-P = 8.2 Hz, 1H), 6.48 (dd, JH-P = 8.2, 3.7 Hz, 1H), 5.92
(s, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 1.13 (d, JH-P = 12.4 Hz, 9H); 13C NMR (125 MHz, CDCl3) δ 165.4,
163.5 (d, JC-P = 1.9 Hz), 162.2 (d, JC-P = 11.8 Hz), 158.7 (d, JC-P = 14.6 Hz), 138.9 (d, JC-P = 1.2 Hz),
132.3, 111.1 (d, JC-P = 3.8 Hz), 109.6 (d, JC-P = 17.5 Hz), 108.7 (d, JC-P = 2.6 Hz), 104.2, 103.1 (d, JC-P
=
1.9 Hz), 85.8 (d, JC-P = 27.0 Hz), 55.4, 53.1, 33.3 (d, JC-P = 22.4 Hz), 27.2 (d, JC-P = 14.3 Hz); 31P NMR
(200 MHz, CDCl3) δ 14.24; HRMS (ESI) m/z (M + H+) 332.1401, calc. for C18H23NO3P 332.1410.
2-((2R,3R)-3-(tert-butyl)-4-methoxy-2,3-dihydrobenzo[d][1,3]oxaphosphol-2-yl)-6-phenylpyridine
(5f). 386 mg white solid, 65% yield. 1H NMR (500 MHz, CDCl3) δ 8.02-8.04 (m, 2H), 7.60 (t, J = 7.8 Hz,
1H), 7.55-7.52 (m, 1H), 7.46-7.43 (m, 2H), 7.40-7.37 (m, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.09 (d, J = 7.7
Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.50 (dd, J = 8.2, 3.6 Hz, 1H), 6.14 (s, 1H), 3.80 (s, 3H), 1.17 (d, J =
12.4 Hz, 9H); 13C NMR (125 MHz, CDCl3) δ 165.4, 162.2 (d, JC-P = 11.7 Hz), 161.2 (d, JC-P = 14.8 Hz),
156.5 (d, JC-P = 1.9 Hz), 139.2, 137.3 (d, JC-P = 1.2 Hz), 132.4, 128.9, 128.6, 126.9, 118.2 (d, JC-P = 2.6
Hz), 117.2 (d, JC-P = 3.5 Hz), 109.6 (d, JC-P = 17.7 Hz), 104.2, 103.2 (d, JC-P = 2.0 Hz), 86.3 (d, JC-P = 27.3
Hz), 55.4, 32.5 (d, JC-P = 22.4 Hz), 27.3 (d, JC-P = 14.2 Hz); 31P NMR (200 MHz, CDCl3) δ 14.52; HRMS
(ESI) m/z (M + H+) 378.1600, calc. for C23H25NO2P 378.1617.
General procedure for the synthesis of iridium complexes
{2-((2R,3R)-3-(tert-butyl)-4-methoxy-2,3-dihydrobenzo[d][1,3]oxaphosphol-2-yl)pyridine}(η4-1,5-
cyclooctadiene)iridium (I) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (6a). A solution of 5a (100
mg, 0.332 mmol) and [IrCl(COD)]2 (115.0 mg, 0.166 mmol) in degassed CH2Cl2 (6 mL) was heated for 1
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h at 45 °C under argon. After cooling to rt, NaBArF (318 mg, 0.348 mmol) was added followed
immediately by 10 ml of degassed water. The two layers were stirred vigorously for 30 min. After
separation of the layers, the aqueous layer was extracted twice with CH2Cl2 (2 mL). The combined
organic layer was dried over Na2SO4 and concentrated to 1 mL. The mixture was then passed through a
short plug of silica under argon using CH2Cl2 as eluent. The center of the first orange fraction was
collected and dried to give 413 mg of 6a as a red-orange solid, 85% yield. 1H NMR (500 MHz, CD2Cl2) δ
8.09 (d, J = 6.0 Hz, 1H), 8.05 (t, J = 7.6 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.63 (s, BArF), 7.47 (s, BArF),
7.42 (t, J = 6.8 Hz, 1H), 7.32 (t, J = 8.3 Hz, 1H), 6.52-6.55 (m, 2H), 5.96 (s, 1H), 5.25-5.28 (m, 1H), 5.05
(m, 1H), 4.83-4.88 (m, 1H), 4.41-4.43 (m, 1H), 3.84 (s, 3H), 2.61-2.65 (m, 1H), 2.30-2.42 (m, 2H), 2.22-
2.28 (m, 2H), 2.01-2.07 (m, 1H), 1.72-1.86 (m, 2H), 1.15 (d, JH-P = 16.2 Hz, 9H); 13C NMR (125 MHz,
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CD2Cl2) δ 164.7 (d, JC-P = 10.0 Hz), 162.7 (d, JC-P = 4.1 Hz), 161.5 (q, 1JC-B = 50.2 Hz), 160.4 (d, JC-P
=
5.5 Hz), 147.8, 140.6 (d, JC-P = 0.9 Hz), 135.3 (d, JC-P = 1.4 Hz), 134.0 (br), 128.2 (qq, 2JC-F = 31.4 Hz,
4JC-F = 2.8 Hz), 127.0, 126.4 (d, JC-P = 7.4 Hz), 125.7, 124.9 (q, 1JC-F = 272.3 Hz), 116.7 (sept, 3JC-F = 4.0
Hz), 105.2 (d, JC-P = 4.0 Hz), 104.4 (d, JC-P = 5.2 Hz), 94.6 (d, JC-P = 9.7 Hz), 93.4 (d, JC-P = 13.7 Hz),
84.8 (d, JC-P = 24.2 Hz), 63.9 (d, JC-P = 19.8 Hz), 55.1, 34.7 (d, JC-P = 4.5 Hz), 34.5 (d, JC-P = 22.1 Hz),
29.9 (d, JC-P = 1.9 Hz), 29.8 (d, JC-P = 1.9 Hz), 25.5 (d, JC-P = 2.4 Hz), 25.4 (d, JC-P = 4.5 Hz); 31P NMR
(200 MHz, CD2Cl2) δ 47.33 (s); HRMS (ESI) m/z 602.1853 (M+), calc. for [IrC25H32NO2P]+ 602.1795;
863.0658 (BArF-), calc. for [C32H12BF24]- 863.0654.
{2-((2R,3R)-3-(tert-butyl)-4-phenyl-2,3-dihydrobenzo[d][1,3]oxaphosphol-2-yl)pyridine}(η4-1,5-
cyclooctadiene)iridium (I) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (6b). 375 mg red-orange
solid, 75% yield. 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 6.0 Hz, 1H), 7.88-7.92 (m, 2H), 7.63 (s,
BArF), 7.39-7.47 (m, 5H), 7.43 (s, BArF), 7.36 (t, J = 7.8 Hz, 1H), 7.29 (dt, J = 6.5, 2.0 Hz, 1H), 6.95 (d,
J = 8.3 Hz, 1H), 6.88 (dd, J = 7.5, 4.0 Hz, 1H), 5.86 (s, 1H), 4.90 (m, 1H), 4.75 (m, 1H), 4.26 (m, 1H),
3.69 (m, 1H), 2.36-2.43 (m, 1H), 2.25-2.31 (m, 2H), 2.05-2.16 (m, 2H), 1.85-2.91(m, 2H), 1.77-1.81 (m,
1H), 0.91 (d, JH-P = 15.9 Hz, 9H); 13C NMR (125 MHz, CDCl3) δ 163.9 (d, JC-P = 9.7 Hz), 161.5 (d, JC-P
4.7 Hz), 161.2 (q, 1JC-B = 50.2 Hz), 147.1, 145.4 (d, JC-P = 9.5 Hz), 140.1, 139.8 (d, JC-P = 1.8 Hz), 133.7
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(br), 133.4 (d, JC-P = 1.8 Hz), 128.2, 128.0 (qq, 2JC-F = 31.6 Hz, 4JC-F = 3.0 Hz), 127.8, 127.6, 125.7 (d, JC-
P = 6.6 Hz), 125.5, 125.3 (d, JC-P = 7.0 Hz), 124.6 (q, 1JC-F = 272.8 Hz), 116.4 (sept, 3JC-F = 4.0 Hz), 113.1
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(d, JC-P = 38.2 Hz), 111.5 (d, JC-P = 3.8 Hz), 93.0 (d, JC-P = 14.3 Hz), 92.6 (d, JC-P = 9.1 Hz), 83.0 (d, JC-P
24.5 Hz), 67.1, 63.1, 34.1 (d, JC-P = 19.9 Hz), 33.4 (d, JC-P = 4.6 Hz), 30.4 (d, JC-P = 2.2 Hz), 28.8 (d, JC-P
=
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= 1.7 Hz), 26.3 (d, JC-P = 2.7 Hz), 25.5 (d, JC-P = 4.1 Hz); 31P NMR (200 MHz, CDCl3) δ 47.12 (s); HRMS
(ESI) m/z 648.2047 (M+), calc. for [IrC30H34NOP]+ 648.2002; 863.0632 (BArF-), calc. for [C32H12BF24]-
863.0654.
{2-((2R,3R)-3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphol-2-
yl)pyridine}(η4-1,5-cyclooctadiene)iridium (I) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (6c).
418 mg red-orange solid, 86% yield. 1H NMR (500 MHz, CD2Cl2) δ 8.19 (d, J = 6.0 Hz, 1H), 7.98-8.03
(m, 2H), 7.64 (s, BArF), 7.47 (s, BArF), 7.41 (dt, J = 6.9, 1.8 Hz, 1H), 7.31-7.35 (m, 2H), 6.95 (d, J = 8.0
Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 7.6, 3.9 Hz, 1H ), 6.62 (d, J = 8.4 Hz, 1H), 5.93 (s, 1H),
4.77-4.83 (m, 1H), 4.37-4.40 (m, 1H), 4.19-4.20 (m, 1H), 3.60-3.65 (m, 1H), 3.62 (s, 3H), 3.55 (s, 3H),
2.38-2.45 (m, 2H), 1.89-2.22 (m, 4H), 1.48-1.56 (m, 2H), 1.06 (d, JH-P = 15.8 Hz, 9H); 13C NMR (125
MHz, CD2Cl2) δ 165.4 (d, JC-P = 9.5 Hz), 162.8 (d, JC-P = 4.5 Hz), 162.3 (q, 1JC-B = 50.4 Hz), 157.8 (d, JC-P
= 25.7 Hz), 148.4, 141.4, 139.8 (d, JC-P = 10.3 Hz), 135.1 (br), 134.2 (d, JC-P = 1.8 Hz), 130.7, 129.4 (qq,
2JC-F = 31.6 Hz, 4JC-F = 2.9 Hz), 127.2 (d, JC-P = 1.7 Hz), 127.1, 126.8, 126.0 (q, 1JC-F = 272.7 Hz), 118.2,
117.8 (sept, 3JC-F = 4.2 Hz), 112.1 (d, JC-P = 3.9 Hz), 104.6 (d, JC-P = 17.4 Hz), 93.4 (d, JC-P = 7.7 Hz),
89.6 (d, JC-P = 16.8 Hz), 84.5 (d, JC-P = 24.8 Hz), 67.6, 65.3, 56.3, 55.7, 36.9 (d, JC-P = 5.5 Hz), 34.8 (d, JC-
P = 20.6 Hz), 32.9, 29.9, 26.3 (d, JC-P = 4.1 Hz), 25.6 (d, JC-P = 2.9 Hz); 31P NMR (200 MHz, CD2Cl2) δ
50.30 (s); HRMS (ESI) m/z 708.2173 (M+), calc. for [IrC32H38NO3P]+ 708.2213; 863.0680 (BArF-), calc.
for [C32H12BF24]- 863.0654.
{2-((2R,3R)-4-(anthracen-9-yl)-3-(tert-butyl)-2,3-dihydrobenzo[d][1,3]oxaphosphol-2-
yl)pyridine}(η4-1,5-cyclooctadiene)iridium (I) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (6d).
427 mg red-orange solid, 82% yield. 1H NMR (500 MHz, CDCl3) δ 8.56 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H),
8.12 (d, J = 5.2 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.89-7.95 (m, 2H), 7.63 (s, BArF), 7.59 (d, J = 8.7 Hz,
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2H), 7.37-7.51 (m, 4H), 7.44 (s, BArF), 7.13 (d, J = 8.2 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 6.3
Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 5.94 (s, 1H), 4.46-4.52 (m, 1H), 3.99-4.05 (m, 1H), 3.68-3.75 (m, 1H),
2.35-2.41 (m, 1H), 1.89-1.95 (m, 1H), 1.68-1.81 (m, 3H), 1.49-1.56 (m, 1H), 1.07-1.17 (m, 2H), 0.88 (d, J
= 15.9 Hz, 9H); 13C NMR (125 MHz, CDCl3) δ 163.5 (d, JC-P = 9.5 Hz), 161.5 (d, JC-P = 4.5 Hz), 160.1 (q,
1JC-B = 49.8 Hz), 147.2, 141.7 (d, JC-P = 10.2 Hz), 140.1, 133.7 (br), 132.1, 130.6 (d, JC-P = 32.2 Hz), 129.3,
128.9, 128.8, 128.0, 127.9 (qq, 2JC-F = 31.4 Hz, 4JC-F = 3.0 Hz), 127.5, 127.2 (d, JC-P = 7.1 Hz), 126.7,
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125.9, 125.7 (d, JC-P = 6.6 Hz), 125.6, 125.2 (d, JC-P = 5.1 Hz), 124.9 (d, JC-P = 11.6 Hz), 124.6 (q, 1JC-F
273.0 Hz), 124.2, 117.6 (d, JC-P = 37.5 Hz), 116.5 (sept, 3JC-F = 4.0 Hz), 112.0 (d, JC-P = 3.7 Hz), 92.1 (d,
=
JC-P = 7.6 Hz, COD, CH), 89.6 (d, JC-P = 16.2 Hz, COD, CH), 83.6 (d, JC-P = 24.9 Hz), 65.2 (COD, CH),
62.1 (COD, CH), 33.4 (d, JC-P = 5.2 Hz, COD, CH2), 33.2 (d, JC-P = 20.2 Hz), 31.0 (COD, CH2), 28.2
(COD, CH2), 25.5 (d, JC-P = 4.1 Hz), 23.6 (d, JC-P = 3.0 Hz, COD, CH2); 31P NMR (200 MHz, CDCl3) δ
47.67 (s); HRMS (ESI) m/z 748.2315 (M+), calc. for [IrC31H36NO2P]+ 748.2313; 863.0654 (BArF-), calc.
for [C32H12BF24]- 863.0654.
Complex 6e. After addition of NaBArF, the mixture was stirred at rt for 12 h until 31P NMR indicated
complete conversion. 431 mg light yellow solid was isolated in 87% yield after the same work up as
above. 1H NMR (500 MHz, CDCl3) δ 7.69 (s, BArF), 7.64 (t, J = 8.1 Hz, 1H), 7.49 (s, BArF), 7.45 (t, J =
8.5 Hz, 1H), 7.32 (dd, 3JH-P = 7.1 Hz, J = 5.1 Hz, 1H, OCH2), 7.23 (d, J = 7.1 Hz, 1H), 6.89 (dd, J = 8.7,
1.0 Hz, 1H), 6.72 (m, 1H, OCH2), 6.69 (t, J = 4.0 Hz, 1H), 6.66 (dd, J = 8.4, 1.8 Hz, 1H), 6.50 (d, J = 6.3
Hz, 1H), 4.37-4.39 (m, 1H), 4.29-4.31 (m, 2H), 3.96 (s, 3H), 3.87-3.90 (m, 1H), 2.57-2.62 (m, 2H), 2.18-
2.32 (m, 2H), 1.95-2.01 (m, 1H), 1.71-1.75 (m, 1H), 1.51-1.53 (m, 1H), 1.21 (d, J =17.0 Hz, 9H), 0.83-
0.93 (m, 1H), -13.34 (dd, 2JH-P = 22.8 Hz, J = 3.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 167.9 (d, JC-P
9.3 Hz), 162.5 (d, J = 6.3 Hz), 162.3 (q, 1JC-B = 50.2 Hz), 160.3 (d, JC-P = 3.8 Hz), 153.1 (d, JC-P = 7.8 Hz),
141.6 (d, JC-P = 1.4 Hz), 136.5 (d, JC-P = 1.7 Hz), 134.8 (br), 129.0 (qq, 2JC-F = 31.5 Hz, 4JC-F = 2.8 Hz),
125.6 (q, 1JC-F = 272.7 Hz), 117.7 (d, JC-P = 9.5 Hz), 117.4 (sept, 3JC-F = 4.1Hz), 111.1, 106.7 (d, JC-P = 3.8
Hz), 105.6 (d, JC-P = 5.4 Hz), 104.3 (d, JC-P = 38.2 Hz), 101.2 (t, JC-P = 2.3 Hz), 95.2 (t, JC-P = 1.9 Hz,
COD, CH), 93.7 (d, JC-P = 29.0 Hz, COD, CH), 68.0 (d, JC-P = 1.9 Hz, COD, CH), 65.3 (d, JC-P = 3.6 Hz,
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COD, CH), 61.6 (dd, J = 57.0, 0.8 Hz, CH2O), 55.7, 34.2 (dd, JC-P = 24.8, 0.8 Hz), 32.8 (d, JC-P = 4.5 Hz,
COD, CH2), 31.7 (COD, CH2), 26.3 (d, J = 3.6 Hz, COD, CH2), 25.8 (COD, CH2), 25.4 (d, JC-P = 3.6 Hz);
31P NMR (200 MHz, CDCl3) δ 46.45 (d, J = 6.5 Hz); HRMS (ESI) m/z 632.1863 (M+), calc. for
[IrC26H34NO3P]+ 632.1900; 863.0648 (BArF-), calc. for [C32H12BF24]- 863.0654.
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Complex 6f. The mixture was stirred at rt for 30 min after addition of NaBArF. Complete conversion was
observed by 31P NMR. 404 mg light yellow solid was isolated in 79% yield. 1H NMR (400 MHz, CDCl3)
δ 8.22 (dd, J = 7.9, 5.4 Hz, 1H), 7.96 (dd, J = 8.4, 1.3 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.79 (td, J = 7.8,
1.7 Hz, 1H), 7.69 (br s, BArF), 7.62 (dd, J = 7.4, 1.4 Hz, 1H), 7.52 (m, 2H), 7.49 (br s, BArF), 7.36 (t, J =
7.8 Hz, 1H), 6.69-6.74 (m, 2H), 6.59 (d, J = 6.3 Hz, 1H), 4.85-4.91 (m, 1H), 4.45-4.49 (m, 2H), 3.99 (s,
3H), 3.19 (br t, J = 8.1 Hz, 1H), 2.74-2.80 (m, 1H), 2.33-2.43 (m, 2H), 1.88-2.06 (m, 2H), 1.61-1.63 (m,
1H), 1.20 (d, J = 17.6 Hz, 9H), 0.82-1.04 (m, 2H), -13.09 (d, 2JH-P = 19.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 166.4 (d, JC-P = 6.3 Hz), 162.6 (d, JC-P = 6.8 Hz), 161.5 (q, 1JC-B = 50.0 Hz) , 160.2 (d, JC-P = 3.6
Hz), 156.3 (d, JC-P = 9.3 Hz), 149.6, 148.9, 145.2, 139.7, 137.6, 136.8 (d, JC-P = 1.4 Hz), 134.7 (br), 131.9
(d, JC-P = 5.0 Hz), 129.3 (qq, 2JC-F = 31.2 Hz, 4JC-F = 3.0 Hz), 127.3 (d, JC-P = 2.8 Hz), 125.8 (q, 1JC-F
=
272.6 Hz), 124.7, 122.7 (d, JC-P = 9.3 Hz), 121.4, 117.4 (sept, 3JC-F = 3.9 Hz), 106.9 (d, JC-P = 3.7 Hz),
105.9 (d, JC-P = 5.2 Hz), 105.4, 104.8 (d, JC-P = 38.7 Hz), 93.1 (d, JC-P = 29.4 Hz, COD, CH), 92.1 (COD,
CH), 73.8 (d, JC-P = 1.5 Hz, COD, CH), 72.0 (d, JC-P = 4.0 Hz, COD, CH), 55.8, 34.6 (d, JC-P = 24.6 Hz),
34.3 (d, JC-P = 5.2 Hz, COD, CH2), 29.1 (COD, CH), 29.0 (COD, CH), 25.3 (COD, CH), 25.2 (d, JC-P
=
3.6 Hz); 31P NMR (160 MHz, CDCl3) δ 49.72 (d, J = 4.0 Hz); HRMS (ESI) m/z 678.2071 (M+), calc. for
[IrC31H36NO2P]+ 678.2107; 863.0671 (BArF-), calc. for [C32H12BF24]- 863.0654.
General procedure for asymmetric hydrogenation of alkenes. A high pressure steel autoclave (HEL
CAT 24) with a glass insert equipped with a magnetic stir bar was taken into a glove box. The glass insert
was loaded with alkene 7a (20 mg, 0.138 mmol), freshly prepared catalyst 6a (4.0 mg, 0.0028 mmol) and
0.5 mL CH2Cl2. The vessel was sealed and taken out of the box. The reactor was purged with N2 and then
H2, and stirred under 400 psi H2 and rt for 18 h. The reactor was then vented. The reaction conversion and
enantiomeric ratio were determined by chiral analysis.22
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ACKNOWLEDGEMENTS
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The authors thank Mr. Keith McKellop and Mr. Scott Pennino for HRMS analyses. We thank one of the
reviewers for the helpful comments on the complex structures.
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Supporting Information
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Copies of 1H and 13C NMR spectra of the compounds, crystallographic data of 4a and chiral HPLC
analyses of 4e and 5e. This material is available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
(1) For reviews, see: (a) Palmer, A. M.; Zanotti-Gerosa, A. Curr. Opin. Drug Discov. Devel. 2010, 13, 698. (b)
Shang, G.; Li, W.; Zhang, X. In Catalytic Asymmetric Synthesis 3rd Edition; Ojima, I., Ed.; Wiley: Hoboken,
2010; pp 343-436. (c) Lennon, I. C.; Moran, P. H. Curr. Opin. Drug Discov. Devel. 2003, 61, 855. (d) Blaser,
H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal. 2003, 345, 103. (e) Busacca,
C. A.; Senanayake, C. H. In Comprehensive Chirality; Carreira, E.; Yamamoto H., Ed.; Elsevier: Frankfurt, 2012;
pp 167-216.
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(14) Crystallographic data for compound 4a was deposited in the Cambridge Crystallographic Data Centre CCDC
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min and 3.49 min. The chiral analysis of the corresponding free ligand 5e was determined by HPLC Chiralpak
AD-H, 4.6 × 250 mm, 3.75 min and 4.13 min. See the Supporting Information for details.
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Commun. 2014, 50, 685. (b) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig J. F. J. Am. Chem. Soc. 2003, 125,
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(22) 8a: chiral GC analysis using Chiraldex B-PH 30 m × 0.25 mm × 0.12 μm column at 90 °C and 1.0 mL/min,
13.61 min and 13.89 min; 8b: chiral HPLC analysis using Chiralcel OJ-3 column 4.6 × 150 mm,
heptane/ethanol = 99:1, 0.9 ml/min, 4.25 min and 6.55 min; 8c: chiral GC analysis using Chiraldex B-PH
column at 150 °C and 1.0 mL/min, 10.39 min and 10.99 min; 8d: chiral GC analysis using Chiraldex B-PH
column at 120 °C and 1.0 mL/min, 10.22 min and 10.55 min; 8e: chiral HPLC analysis using Chiralcel OJ-H,
heptane/iPrOH = 95/5, 1.0 mL/min, IPA as diluent, 4.52 min and 4.84 min.
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