Synthesis and Applications of HexaPHEMP, a Novel Biaryl Diphosphine Ligand

Article abstract of DOI:10.1002/adsc.200390025

The novel biaryldiphosphine ligand 1 (HexaPHEMP) has been prepared in five steps from commercially available 3,4,5-trimethylphenol using a concise synthetic route. This approach also allows fine tuning of the ligand's stereoelectronic properties through t

Full text of DOI:10.1002/adsc.200390025

FULL PAPERS
Synthesis and Applications of HexaPHEMP, a Novel Biaryl
Diphosphine Ligand
Julian P. Henschke,* Mark J. Burk,a Christophe G. Malan,b Daniela Herzberg,
Justine A. Peterson, Andrew J. Wildsmith, Christopher J. Cobley, Guy Casy*
Pharmaceutical Services, Chirotech Technology Limited (a Subsidiary of The Dow Chemical Company), 321 Cambridge
Science Park, Milton Road, Cambridge, CB4 0WG, UK
Fax: ( ‡ 44)-1223-506-701, e-mail: gcasy@dow.com
a
Current address: Diversa Corporation, 4955 Directors Place, San Diego, California 92121, USA
Current address: BU Catalysis Development, Solvias AG, Klybeckstrasse 191, WRO-1055.6.22, 4002 Basel, Switzerland
b
Received: August 8, 2002; Accepted: October 18, 2002
Abstract: The novel biaryldiphosphine ligand 1 (Hexa- ligand were found to have enhanced activity and
PHEMP) has been prepared in five steps from selectivity over other biaryldiphosphine-containing
commercially available 3,4,5-trimethylphenol using a catalysts.
concise synthetic route. This approach also allows fine
tuning of the ligand×s stereoelectronic properties
through the variation of the aromatic groups on the Keywords: asymmetric catalysis; asymmetric hydro-
ligating phosphorus atoms. In certain asymmetric genation; biaryldiphosphine; HexaPHEMP; P-li-
hydrogenation processes, catalysts containing this gands; ruthenium
Introduction
(2a) and analogues, MeO-BIPHEP[3] (3) and BI-
TIANP[4] (4) (Figure 1) are representative of the few
The development of chiral ligands required for the chiral biaryldiphosphines that have been developed
preparation of highly active and enantioselective tran- sufficiently for large-scale industrial use. In a quest to
sition metal catalysts remains of great interest and value. develop an accessible biaryldiphosphine ligand that
In particular, atropisomeric biaryldiphosphines have forms catalytically active complexes with transition
been utilised effectively in the asymmetric hydrogena- metals, having equal or improved activity and selectivity
tion of a variety of functionalities including ketones, to equivalent complexes of known biaryldiphosphine
imines, a-keto esters, b-keto esters, b-diketones, a,b- ligands, we prepared a series of ligands based on the
unsaturated carboxylic acids, b-dehydroamino acids, 4,4',5,5',6,6'-hexamethybiphenyl (HexaPHEMP) back-
itaconates, enamides and unsaturated alcohols.[1] Al- bone 1.[5] Herein, we outline the synthesis and prelimi-
though a very large number of chiral biarylphosphine nary catalytic results associated with these ligands.
ligands have been prepared and investigated in small
quantities for research, fewer have been developed
commercially, and in such context the synthetic acces- Results and Discussion
sibility can often be a limiting factor. In fact, BINAP[2]
Synthesis of HexaPHEMP Ligands
S
The route used to synthesiseHexaPHEMP (1a) is shown
in Scheme 1. We anticipated that symmetric 3,4,5-
PPh2
PAr2
PAr2
PAr2 MeO
PAr2 MeO
PPh2
PPh2
trisubstituted phenol 5 would provide straightforward
access to biphenol derivatives through oxidative cou-
pling. Indeed, oxidative coupling of 3,4,5-trimethylphe-
PPh2
S
[6]
nol (5) using 5 mol % VO(acac)2 under a constant
1a (Ar = Ph)
1b (Ar = Xyl)
2a (Ar = Ph)
3
4
stream of air at r.t. for 48 h furnished the racemic
biphenol 6 in 74% isolated yield. This was subsequently
resolved by chiral HPLC (Chiral Technologies Europe).
This reaction and separation were readily conducted on
2b (Ar = p-Tol)
2c (Ar = Xyl)
Figure 1. Biaryldiphosphine ligands prepared at industrially
useful scale.
300
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/03/3451+2-300 307 $ 17.50-.50/0
Adv. Synth. Catal. 2003, 345, No. 1+2

Synthesis and Applications of HexaPHEMP, a Novel Biaryl Diphosphine Ligand
FULL PAPERS
a 90 g scale. Each diol enantiomer was converted to the respectively. Although the palladium-catalysed cou-
enantiomerically pure phosphine products separately pling proceeded well, the nickel-catalysed step ap-
and only the (R)-enantiomer is discussed below. Enan- peared more difficult and afforded a mixture of (S)-
tiomerically pure (R)-biphenol 6 was converted to the Xyl-HexaPHEMP (1b) and the Xyl-phosphine mono-
corresponding (R)-bis-triflate 7 using Tf2O and pyridine triflate starting material 9b. The mixture was treated
in 95% yield following recrystallisation from methanol. with TBAF providing a chromatographically separable
Since our attempts to then introduce two phosphine mixture of (S)-Xyl-HexaPHEMP (1b) and phenol 10.
groups simultaneously were unsuccessful, a stepwise The purified (S)-ligand 1b was a white solid that showed
approach was used. The first phosphine group was a single resonance in the 31P NMR spectrum at À 13.0
introduced via Pd(OAc)2 (4 mol %)-catalysed cross- ppm. We have also confirmed that the non-C2-symmet-
coupling of Ph2P(O)H and (R)-bis-triflate 7 in the ric mixed phosphine ligand 1c can be prepared using a
presence of 1,4-bis(diphenylphosphino)butane (dppb) NiCl2dppe-catalysed coupling of Xyl2PH with racemic
and H¸nig×s base in essentially quantitative yield.[7] This monotriflate 9a.
reaction was readily conducted on 75 g of starting
material 7. The phosphine oxide monotriflate 8a was
reduced using HSiCl3 in the presence of Et3N, giving Asymmetric Hydrogenations using HexaPHEMP-
phosphine monotriflate (R)-9a in 77% yield over two Based Catalysts
steps from bis-triflate 7. The second phosphine group
was introduced using a nickel-catalysed cross-cou- With the requisite ligands in hand we prepared a series
pling.[8] Thus, reaction of triflate 9a with Ph2PH in the of precatalysts for evaluation of the HexaPHEMP back-
presence of NiCl2dppe (10 mol %) and DABCO gave bone with several hydrogenation substrates.
enantiomerically pure HexaPHEMP (R)-1a in 74%
yield. This reaction was conducted on a 60 g scale. The
purified (R)-and (S)-HexaPHEMP ligands prepared b-Enamides
using this procedure were white solids that showed
single resonances in their 31P{1H} NMR spectra at Few examples of b-amino acid syntheses via asymmetric
À 13.3 ppm.
hydrogenation of b-acetamidocrotonates have been
The Xyl-HexaPHEMP analogue 1b (Xyl ˆ 3,5-dime- reported,[9,10,11] and only Noyori[9] has used ruthenium-
thylphenyl) was prepared as for HexaPHEMP (1a) by based catalysts for this purpose. Wesought to investigate
substituting Ph2P(O)H and Ph2PH in the palladium and the efficiency of the ruthenium precatalyst system
nickel coupling steps with (Xyl)2P(O)H and Xyl2PH, Ru(CF3CO2)2[(S)-HexaPHEMP], prepared using anal-
i, ii
iii
iv
P(O)Ar2
OTf
OH
OH
OTf
OTf
OH
5
6 (74%)
7 (95%)
8a (Ar = Ph; 86%)
8b (Ar = Xyl; 74%)
v
PAr2
PAr2
PAr2
OTf
vi
PXyl2
OH
1a (Ar = Ph; 74%)
1b (Ar = Xyl; ca. 50% from 8b) 9b (Ar = Xyl; not purified)
9a (Ar = Ph; 90%)
10
rac-1c (Ar = Ph, Xyl; 87%)
For 1a: (i) V(O)(acac)2 (5 mol %), DCM, air, 48 h, r.t.; (ii) Chiral HPLC; (iii) Tf2O (2.3 equiv.), pyridine
(2.5 equiv.), DCM, 18 h, r.t.; (iv) Ph2P(O)H (1.15 equiv.), Pd(OAc)2 (4 mol %), dppb (4 mol %), i-Pr2NEt
(2.0 equiv.), DMSO, 110 °C, 16 h; (v) HSiCl3 (5 equiv.), Et3N (10 equiv.), toluene, reflux, 4 h; (vi)
Ph2PH (1.5 equiv.), Ni(dppe)Cl2 (10 mol %), DABCO (2.0 equiv.), DMF, 110 °C, 16 h.
Scheme 1. Synthesis of HexaPHEMP ligands.
Adv. Synth. Catal. 2003, 345, 300 307
301

Julian P. Henschke et al.
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Table 1. Asymmetric hydrogenation of (E)-ethyl b-acetamidocrotonate (11).[a]
Entry
Diphosphine
S/C
100
100
10,000
100
Time
Conversion [%]
ee [%]
1
2
3
4
5
6
(R,R)-i-Pr-DuPHOS
(R)-BINAP
(R)-BINAP
(S)-HexaPHEMP
(S)-HexaPHEMP
(S)-HexaPHEMP
30 min
<2 min
16 h
<1 min
<1 min
16 h
>99
>99
>99
>99
>99
75
39 (R)
93 (S)
95 (S)
95 (R)
95 (R)
95 (R)
1,000
10,000
[a]
Reactions were conducted at 140 psi H2, r.t. in MeOH. Conversion and ees were determined by GC analysis (Chirasil DEX-
CB column). Absolute configuration is in parentheses.
Table 2. Precatalyst screening against neat 2-methylquinoxaline (13).[a]
Entry
Diphosphine
Diamine
Conversion [%]
ee [%]
1
2
3
4
5
6
7
8
(R,R)-Et-DuPHOS
(R)-BINAP
(R)-BINAP
(S)-HexaPHEMP
(S)-Xyl-HexaPHEMP
(S)-BINAP
(S)-HexaPHEMP
(S)-Xyl-HexaPHEMP
(R,R)-DACH
(R)-DAIPEN
(R,R)-DPEN
(S,S)-DPEN
(S,S)-DPEN
(S,S)-DACH
(S,S)-DACH
(S,S)-DACH
98
94
99
>99
>99
>99
>99
99
40 (S)
62 (S)
66 (S)
69 (R)
72 (R)
61 (S)
65 (R)
73 (R)
[a]
Reactions were conducted with neat 15 (5.6 M), at 430 psi H2, 508C, S/C/B 1000/1/50, 20 h, 0.05 equiv. 1.0 M t-BuOK in t-
BuOH. Conversion and ees were determined by GC analysis (Chirasil DEX-CB column). Absolute configuration is in
parentheses.
ogous literature methods,[12] for reduction of (E)-ethyl challenging class of substrates.[5,16,17] We examined the
b-acetamidocrotonate (11) in comparison to catalysts asymmetric hydrogenation of the heteroaromatic di-
prepared from other diphosphines (Table 1). The (S)- imine 13 and found that the HexaPHEMP-based
HexaPHEMP-based catalyst was highly active at molar catalysts (Table 2; entries 4, 5, 7 and 8) provided slightly
substrate-to-catalyst (S/C) ratios of 100, 1,000 and improved selectivity over BINAP-based systems (en-
10,000/1, and was found to give similar performance to tries 2, 3 and 6). Interestingly, our Et-DuPHOS-based
the (R)-BINAP catalyst (entries 2 and 3) but was catalyst (entry 1), which was found to be very selective
significantly better than our (R,R)-i-Pr-DuPHOS[13] for another imine substrate,[16] performed poorly for the
catalyst (entry 1).
asymmetric hydrogenation of diimine 15. A small
improvement in the selectivity was achieved by use of
the more electron-rich Xyl-HexaPHEMP-based cata-
lysts (entry 5 and 8). It is worth noting that an iridium-
based catalyst reported by Bianchini et al.[18] provided a
com- 73% ee with 97% yield for this particularly challenging
Imines
Noyori×s
RuCl2[diphosphine][1,2-diamine]
plexes[14] are excellent precatalysts for the asymmetric substrate.
homogeneous hydrogenation of simple ketones, not
requiring the presence of secondary binding function-
ality.[15] These precatalysts are converted into active Ketones
catalysts by treatment with excess base (e.g., t-BuOK) in
situ. These ruthenium complexes can also be used for the Among the various diphosphines that have been exam-
asymmetric hydrogenation of imines[16,17] which are a ined with RuCl2[diphosphine][1,2-diamine] complexes,
302
Adv. Synth. Catal. 2003, 345, 300 307

Synthesis and Applications of HexaPHEMP, a Novel Biaryl Diphosphine Ligand
FULL PAPERS
Table 3. Asymmetric hydrogenation of acetophenone (15).[a]
Entry
R
Diphosphine
Diamine
Time
17 h
Conversion [%]
ee [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
H
H
H
H
H
H
H
H
H
H
3'-CF3
3'-CF3
3'-CF3
(S)-BINAP
(S)-BINAP
(R)-BINAP
(S,S)-DPEN
(S,S)-DACH
(R)-DAIPEN
(R,R)-DPEN
(R,R)-DPEN
(R,R)-DACH
(R)-DAIPEN
(S,S)-DPEN
(S,S)-DACH
(S)-DAIPEN
(S,S)-DPEN
(S,S)-DACH
(S)-DAIPEN
>99
85
85 (R)
82 (R)
86 (S)[b]
84 (S)
86 (S)
86 (S)
90 (S)
99 (R)
96 (R)
99 (R)c
99 (R)
95 (R)
99 (R)[c]
3 h
1 h
12 h
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
(R)-MeO-BIPHEP
(R)-HexaPHEMP
(R)-HexaPHEMP
(R)-HexaPHEMP
(S)-Xyl-HexaPHEMP
(S)-Xyl-HexaPHEMP
(S)-Xyl-HexaPHEMP
(S)-Xyl-HexaPHEMP
(S)-Xyl-HexaPHEMP
(S)-Xyl-HexaPHEMP
1 h
20 min
30 min
61 min
24 min
28 min
56 min
49 min
41 min
[a]
Reactions were conducted at 120 psi H2, r.t., S/C/B 3000/1/50, 20 h, with 0.05 equiv. 1.0 M t-BuOK in t-BuOH. Conversion
and ees were determined by GC analysis (Chirasil DEX-CB column). Absolute configuration is in parentheses.
Noyori et al. reported 87% ee using RuCl2[(S)-BINAP][(S,S)-DAIPEN] precatalyst.[15]
[b]
[c]
Noyori et al. reported 99% ee using RuCl2[(S)-Xyl-BINAP][(S,S)-DAIPEN] precatalyst.[15]
Noyori×s BINAP-based catalysts consistently allow the much higher selectivity. The selectivities obtained using
hydrogenation of prochiral ketones with impressive RuCl2[(S)-Xyl-HexaPHEMP][diamine] (entries 8 to
chemo- and stereoselectivity, very high activity and 13) precatalyst were comparable to those achieved
catalyst efficiency. We have also developed catalysts using our Xyl-PhanePhos-ruthenium catalysts.[20] Al-
based on the PhanePhos[19] ligand that have proven, though the preferred diamine with PhanePhos was
when used in combination with DPEN (1,2-diphenyle- DPEN, DAIPEN was preferred for Xyl-HexaPHEMP-
thylenediamine), to be as effective.[20]
based catalysts.
In order to make direct comparisons between our
results and those achieved with BINAP-ruthenium
catalysts, we performed parallel experiments with both
catalyst systems under identical conditions with the
same substrates. Thus, we prepared ruthenium dichlor-
ide complexes of BINAP (2a), HexaPHEMP (1a) and
Xyl-HexaPHEMP (1b) with DPEN, DACH (trans-1,2-
diaminocyclohexane) and DAIPEN (1,1-dianisyl-2-iso-
propyl-1,2-ethylenediamine) for testing in the asym-
metric hydrogenation of acetophenone 15a and 3'-
trifluoromethylacetophenone 15b (Xyl-HexaPHEMP
only). As is evident from Table 3, the HexaPHEMP-
based catalysts performed consistently better than
BINAP catalysts, particularly in terms of activity under
identical reaction conditions (cf. entries 1 3 and 5 7).
Given that the DACH ligand is a much cheaper diamine
than DAIPEN[21] it was pleasing to observe that the (R)-
HexaPHEMP/(R,R)-DACH system (entry 6) was as
selective as the (R)-BINAP/(R)-DAIPEN system (en-
try 3) but was about three times more active. In another
comparative experiment, a MeO-BIPHEP-based cata-
lyst (entry 4) gave a similar enantiomeric excess and was
markedly less active. Xyl-HexaPHEMP (1b)-based
Conclusion
In conclusion, we have synthesised a novel ligand system
that is useful for producing highly active and enantio-
selective hydrogenation catalysts. In all cases studied,
HexaPHEMP or Xyl-HexaPHEMP performed as well
as or better than the corresponding BINAP ligands. The
oxidative phenolic coupling is greatly facilitated by the
symmetry of 3,4,5-trimethylphenol, which affords a
single clean product. The synthetic approach allows
the incorporation of different phosphorus-containing
moieties into the backbone to produce a family of
ligands, which we are currently investigating.
Experimental Section
General Information
The commercially available diamines DPEN (Fluka) and
DAIPEN (Strem) were used as received. DACH[22] and bis(3,5-
catalysts (entries 8 13) showed similar activity but dimethylphenyl)phosphine oxide[23] were prepared according
Adv. Synth. Catal. 2003, 345, 300 307
303

Julian P. Henschke et al.
FULL PAPERS
to literature procedures. BINAP (Strem) and MeO-BIPHEP
(Fluka) were purchased and used as received. Et-DuPHOS
and i-Pr-DuPHOS were prepared as previously described.[13] 2-
Methylquinoxaline (Aldrich) was distilled before use. The
following reagents were used as received: 3,4,5-trimethylphe-
nol (Lancaster), CH2Cl2 (Fisher; HPLC grade), V(O)(acac)2
(Aldrich), pyridine (Acros; 99% ‡ ), MTBE (Fisher; HPLC
grade), conc. HCl (37%: Fisher), MeOH (Fisher; HPLC
grade), HP(O)Ph2 (Acros; 97%), Pd(OAc)2 (Acros), dppb
(Acros), NEt(i-Pr)2 (Acros; 98% ‡ ), DMSO (Acros; 99.9%;
spectroscopic grade), trichlorosilane (Acros), NEt3 (Aldrich),
PhMe (Fisher; HPLC grade), HPPh2 (Fluka 95%), Ni(dppe)Cl2
(Aldrich), DABCO (Acros 97%), DMF (Acros ‡ 99%), and
cyclohexanone (Acros 99.8%), silica gel (Matrex* Silica 60,
Fisher), Biotage Cartridge (KP Sil 32 63 mm 60 ä silica).
(74.1 g, 0.138 mol), diphenylphosphine oxide (35.2 g, 0.174 mol),
palladium acetate (1.56 g, 0.007 mol), 1,4-bis(diphenylphos-
phino)butane (2.97 g, 0.007 mol) and i-Pr2NEt (67.6 mL, 0.386
mol) were dissolved in DMSO (490 mL) and heated under
nitrogen at 110 8C for 16 h. The reaction mixture was diluted
with EtOAc (3400 mL) and washed twice with 5% HCl (1000
mL) and brine (1000 mL). The combined aqueous layers were
extracted with EtOAc (800 mL). The combined organic layers
were washed with brine and dried over MgSO4. The solvent
was evaporated under reduced pressure to yield the crude
product as a red oil (87.0 g). The title compound was obtained
as a yellow foam after purification by column chromatography
(Biotage 75, eluent EtOAc); yield. 69.9 g (86%). 1H NMR
(CDCl3, 400 MHz): d ˆ 1.75 (s, 3H), 1.89 (s, 3H), 2.07 (s, 3H),
2.23 (s, 3H), 2.25 (s, 3H), 2.26 (s, 3H), 6.55 (s, 1H), 7.13 (d, 1H,
ˆ
JP, H 14.5 Hz), 7.24 7.48 (m, 6H), 7.57 (m, 2H), 7.72 (m, 2H);
13C NMR (CDCl3, 100 MHz): d ˆ 15.7 (CH3), 16.5 (CH3), 17.0
(CH3), 17.9 (CH3), 20.8 (CH3), 21.0 (CH3), 118.2 (CF3), 118.7
(CH), 127.7 (CH), 128.1 (CH), 128.3 (CH), 128.8 (C), 129.8 (C),
130.9 (CH), 131.2 (2 Â CH), 131.3 (CH), 131.6 (2 Â CH),
132.1 (CH), 133.0 (CH), 133.2 (C), 134.0 (C), 134.9 (C), 135.7
(C), 136.4 (C), 137.6 (C), 137.9 (C), 138.8 (C), 140.5 (C), 145.1
(C); 19F NMR (CDCl3, 376 MHz): d ˆÀ 75.6; 31P{1H} NMR
(CDCl3, 162 MHz): d ˆ 29.2.
Ligand Synthesis
4,4',5,5',6,6'-Hexamethyl-2,2'-biphenyldiol (6): 3,4,5-Trime-
thylphenol (76.4 g, 561 mmol) was dissolved in CH2Cl2 (140
mL), vanadyl acetylacetonate (7.44 g, 26.1 mmol) was added
and the reaction was stirred under a constant stream of air for
48 h. The solvent was removed under reduced pressure and the
residue was refluxed in Et2O (300 mL) for 30 min. The mixture
was allowed to cool to À 20 8C for 2 h, before filtering off the
product. The product was further purified by refluxing in
ethanol (100 mL), for 1 h. The solution was again cooled to
À 20 8C for 2 h before filtering. The product (56.1 g, 74%) was
obtained as a white crystalline solid. This was resolved into
constituent enantiomers by preparative chiral HPLC (in
collaboration with Chiral Technologies Europe). 1H NMR
(CDCl3, 400 MHz): d ˆ 1.90 (s, 6H), 2.15 (s, 6H), 2.30 (s, 6H),
4.50 (s, 2H), 6.75 (s, 2H); 13C NMR (CDCl3, 100 MHz): d ˆ 15.4
(CH3), 16.9 (CH3), 20.9 (CH3), 114.4 (CH), 118.0 (C), 127.7 (C),
136.8 (C), 138.4 (C), 151.2 (C).
4,4',5,5',6,6'-Hexamethyl-2-diphenylphosphino-2'-trifluoro-
methanesulfonyloxy-biphenyl (9a): 4,4',5,5',6,6'-Hexamethyl-
2-diphenylphosphinoyl-2'-trifluoromethanesulfonyloxy-bi-
phenyl (69.9 g, 0.119 mol) was dissolved in PhMe (1600 mL)
and Et3N (189 mL, 1.35 mol) was added. The reaction mixture
was cooled to 0 8C and trichlorosilane (68.2 mL, 6.78 mol.) was
added at such a rate as to maintain the reaction temperature
below 78C. The reaction mixture was heated at reflux for 16 h.
The reaction mixture was allowed to cool to room temperature
and excess trichlorosilane was evaporated under vacuum. The
residue was diluted with PhMe (1200 mL) and then washed
sequentially with saturated aqueous NaHCO3 solution (500
mL) and 5% HCl (1000 mL). The combined aqueous washings
were extracted twice with PhMe (1000 mL). The combined
organic layers were washed with brine (1000 mL). The organic
layer was stirred on Carbon (Darco 12 20 mesh, 600 g) and
MgSO4. It was filtered through a pad of Celite (500 mL) and
sand and the solvent was evaporated under reduced pressure to
give 4,4',5,5',6,6'-hexamethyl-2-diphenylphosphino-2'-trifluor-
omethanesulfonyloxy-biphenyl as a pale yellow foam; yield:
The following experiments were conducted with enantio-
merically pure material.
4,4',5,5',6,6'-Hexamethyl-2,2'-bis(trifluoromethanesulfonyl-
oxy)-biphenyl (7): To a cooled suspension of 4,4',5,5',6,6'-
hexamethyl-2,2'-biphenyldiol (39.8 g, 0.147 mol) and pyridine
(30.0mL, 0.368 mol) in CH2Cl2 (550 mL) was added a solution
of trifluoromethanesulfonic anhydride (59.0 mL, 0.349 mol) in
CH2Cl2 (50 mL) at such a rate to maintain the temperature in
the range between 5 10 8C. After the addition was complete
the reaction mixture was allowed to warm slowly to room
temperature and it was stirred for 18 h. The reaction mixture
was diluted with MTBE (2000 mL) and washed twice with 5%
HCl (800 mL) with saturated aqueous NaHCO3 solution
(800mL) and brine (800 mL). It was dried over MgSO4 and the
solvent was evaporated under reduced pressure. After recrys-
tallisation from MeOH (300 mL) 4,4',5,5',6,6'-hexamethyl-2,2'-
bis(trifluoromethanesulfonyloxy)-biphenyl was obtained as a
colourless solid; yielˆd: (4.8 g (95%). 1H NMR (CDCl3,
400 MHz): d ˆ 2.00 (s, 6H), 2.24 (s, 6H), 2.38 (s, 6H), 7.04 (s,
2H); 13C NMR (CDCl3, 100 MHz): d ˆ 16.0 (CH3), 17.6 (CH3),
21.0 (CH3), 118.3 (CF3), 119.7 (CH), 125.9 (C), 136.1 (C), 138.8
(C), 138.9 (C), 145.0 (C); 19F NMR (CDCl3, 376 MHz): d ˆ
À 75.2.
1
60.5 g (90%). H NMR (CDCl3, 400 MHz): d ˆ 1.48 (s, 3H),
1.91 (s, 3H), 2.08 (s, 3H), 2.21 (s, 3H), 2.22 (s, 3H), 2.36 (s, 3H),
6.83 (d, 1H), 6.98 (s, 1H), 7.12 (m, 2H), 7.15 7.27 (m, 8H);
13C NMR (CDCl3, 100 MHz): d ˆ 14.8 (CH3), 15.0 (CH3), 16.0
(CH3), 16.3 (CH3), 16.3 (CH3), 19.9 (CH3), 117.1 (CF3), 118.4
(CH), 126.9 (CH), 127.0 (CH), 127.1 (CH), 127.1 (CH), 127.5
(CH), 131.0 (C), 131.79 (CH), 131.8 (CH), 132.0 (CH), 132.2
(CH), 133.0 (C), 133.2 (CH), 133.4 (CH), 134.3 (C), 134.9 (C),
135.2 (C), 135.9 (C), 136.0 (C), 136.5 (C), 136.5 (C), 137.3 (C),
137.6 (C), 143.8 (C); 19F NMR (CDCl3, 376 MHz): d ˆÀ 75.4;
31P{1H} NMR (CDCl3, 162 MHz): d ˆÀ 11.9.
HexaPHEMP (1a): [1,2-Bis(diphenylphosphino)ethane]di-
chloronickel(II) (5.5 g, 0.0104 mol) was dissolved in degassed
DMF (400 mL). Diphenylphosphine (29.4 g, 0.158 mol) was
added and the reaction mixture was heated at 110 8C for 30
min. In a second flask, 4,4',5,5',6,6'-hexamethyl-2-diphenyl-
phosphino-2'-trifluoromethanesulfonyloxy-biphenyl (60.0 g,
0.105 mol) was dissolved in degassed DMF (400 mL) and 1,4-
4,4',5,5',6,6'-Hexamethyl-2-diphenylphosphinoyl-2'-tri-
fluoromethanesulfonyloxy-biphenyl
(8a):
4,4',5,5',6,6'-
Hexamethyl-2,2'-bis(trifluoromethanesulfonyloxy)-biphenyl
304
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Synthesis and Applications of HexaPHEMP, a Novel Biaryl Diphosphine Ligand
FULL PAPERS
diazabicyclo[2.2.2]octane (23.5 g, 0.209 mol) was added. The
hot catalyst solution was transferred via teflon tubing to the
reaction mixture in the second flask, stirred at room temper-
ature. After the addition was complete the reaction mixture
was stirred at 110 8C for 16 h, then allowed to cool to room
temperature and degassed cyclohexanone (200 mL) was
added. The solvents were evaporated under reduced pressure.
EtOAc was added and a solid was filtered off and washed with
EtOAc. The solvent was evaporated under reduced pressure.
HexaPHEMP was obtained as a colourless solid after purifi-
cation by column chromatography (Biotage 75, eluent EtOAc-
heptane1:3); yield: 46.5 g (74%). 1H NMR (CDCl3, 400 MHz):
d ˆ 1.21 (s, 6H), 2.00 (s, 6H), 2.22 (s, 6H), 6.85 (s, 2H), 7.20 7.26
(m, 20H); 13C NMR (CDCl3, 100 MHz): d ˆ 16.3 (CH3), 17.2
(CH3), 21.4 (CH3), 127.7 (CH), 128.3 128.4 (6 CH), 128.9
(CH), 133.2 133.4 (2 CH, C), 134.6 (C), 135.5 (C), 135.6 (CH),
136.4 (C), 137.7 (C), 139.8 (C), 144.7 (C); 31P{1H} NMR
(CDCl3, 162 MHz): d ˆÀ 13.3.
vacuum with gentle heating, the product was dissolved in
EtOAc (300 mL) and washed with distilled water (200 mL) and
brine (200 mL), dried over MgSO4, filtered and evaporated to
give a white foam. 31P{1H}-NMR analysis indicated that this
was a mixture of the desired product 1b and Xyl-phosphine
monotriflate 9b. A portion of the product mixture (3.0 g) in
THF (60 mL) was treated with 1 M TBAF in THF (5 mol %
water) (4.8 mL, 5.8 mmol) under reflux for 12.5 h. After 3 h
another portion of 1 M TBAF in THF (4.8 mL, 5.8 mmol) was
added to the reaction mixture, followed by a third portion (2.4
mL, 2.9 mmol) after 7.5 h. The mixture was diluted with CH2Cl2
(300 mL) and washed twice with distilled water (200 mL), then
with brine (200 mL), dried over MgSO4, filtered and evapo-
rated to give a yellow foam (2.75 g). This material was
chromatographed over silica gel (eluting with 1% MTBE/
heptane) providing the title product as a white foam; yield: 898
mg (1.25 mmol). 1H NMR (CDCl3, 400 MHz): d ˆ 1.32 (s, 6H),
2.04 (s, 6H), 2.14 (s, 6H), 2.21 (s, 12H), 2.24 (s, 6H), 6.79 (s, 2H),
6.83 6.89 (m, 10H), 6.95 (s, 2H); 13C NMR (CDCl3, 100 MHz):
d ˆ 15.9 (CH3), 17.1 (CH3), 21.0 (CH3), 21.2 (CH3), 21.3 (CH3),
128.9, 130.0, 130.8, 130.9, 132.8, 132.9, 134.9, 135.7, 137.0
(aromatic C and CH); 31P{1H} NMR (CDCl3, 162 MHz): d ˆ
À 13.0.
4,4',5,5',6,6'-Hexamethyl-2-bis(3,5-dimethylphenyl)phos-
phinoyl-2'-trifluoromethylsulfonyloxy-biphenyl
(8b):
4,4',5,5',6,6'-Hexamethyl-2,2'-bis(trifluoromethanesulfonyl-
oxy)-biphenyl (4.00 g, 7.48 mmol), bis(3,5-dimethylphenyl)-
phosphine oxide (2.42 g, 9.35 mmol), palladium acetate (168
mg, 0.75 mmol), 1,4-bis(diphenylphosphino)butane (319 mg,
0.75 mmol) and i-Pr2NEt (3.26 mL, 18.71 mmol) were dissolved
in DMSO (40 mL) and the solution was heated under nitrogen
at 110 8C for 23 h. A mixture of bis(3,5-dimethylphenyl)phos-
phine oxide (1.93 g, 7.48 mmol), palladium acetate (84 mg, 0.37
mmol), 1,4-bis(diphenylphosphino)butane (160 mg, 0.37
mmol) and i-Pr2NEt (1.30 mL, 7.48 mmol) were dissolved in
DMSO (5 mL) and heated under nitrogen at 110 8C until the
mixture became homogenous. This solution was added to the
original reaction mixture, which was then heated under
nitrogen at 110 8C for 22 h. The solvent was evaporated under
high vacuum providing a brown syrup which was chromato-
graphed over silica gel (60% MTBE/heptane) giving the title
compound as a white foam; yield: 3.57 g (5.56 mmol, 74%).
1H NMR (CDCl3, 400 MHz): d ˆ 1.83 (s, 3H), 1.88 (s, 3H), 2.08
(s, 3H), 2.21 (s, 6H), 2.23 (s, 3H), 2.24 (s, 3H), 2.27 (s, 6H), 6.57
(s, 1H), 7.00 (s, 1H), 7.06 (s, 2H), 7.09 (s, 1H), 7.23 (m, 3H);
19F NMR (CDCl3, 376 MHz): d ˆÀ 75.6; 31P{1H} NMR
(CDCl3, 162 MHz): d ˆ 28.9.
Catalyst Preparation
Ru(CF3CO2)2(diphosphine): [RuCOD(CF3CO2)2]2 (14.4 mg,
0.033 mmol) and the respective diphosphine 1 (0.066 mmol)
were placed in a 50 mL Schlenk flask. The entire apparatus was
evacuated and back filled with N2 three times to establish an
inert atmosphere. THF (anhydrous, deoxygenated, 10 mL) was
added and the reaction mixture stirred at 40 8C for 5 h. The
reaction mixture was then reduced to dryness under vacuum
and the resulting tan coloured solid washed with hexane (10
mL). After drying under vacuum for 3 h, 31P{1H}-NMR
spectroscopy (sample prepared under nitrogen using CDCl3)
showed the tan coloured powder to be the desired complex
(assumed to be the H2O-included complex formed in situ whilst
preparing the NMR sample; see ref.[12]).
For (S)-HexaPHEMP based catalyst: 31P{1H} NMR (CDCl3,
162 MHz): d ˆ 55.6 (d, J ˆ 35.2 Hz), 49.5 (d, J ˆ 35.2 Hz).
RuCl2(diphosphine)(diamine): The precatalysts were pre-
pared according to the procedure described by Noyori et al.;[24]
diphosphines were generally allowed to react with the ruthe-
nium dimer for ca. 30-60 min. Diamines were then reacted with
the ruthenium-diphosphine intermediates at room temper-
ature overnight. The DMF was removed under high vacuum at
ca. 70 8C giving tan-coloured solids. These were dissolved in
CH2Cl2 (anhydrous, degassed) and the CH2Cl2 was evaporated
under reduced pressure. This process was repeated, and then
again once with Et2O (anhydrous, degassed).
Xyl-HexaPHEMP (1b): A mixture of 3,3',4,4',5,5'-hexa-
methyl-6-bis(3,5-dimethylphenyl)phosphinyl-6'-trifluorome-
thylsulfonyloxybiphenyl (2.2 g, 3.3 mmol) and trichlorosilane
(6.7 mL, 66.4 mmol) in PhMe (15 mL) was heated at reflux for
16h. The solvent was evaporated to dryness under high vacuum
with gentle heating. The resulting residue of 4,4',5,5',6,6'-
hexamethyl-2-bis(3,5-dimethylphenyl)phosphino-2'-trifluoro-
methylsulfonyloxy-biphenyl was dissolved in degassed DMF
(15 mL) and 1,4-diazabicyclo[2.2.2]octane (560 mg, 5.0 mmol)
was added. In a second flask, [1,2-bis(diphenylphosphino)e-
thane]dichloronickel(II) (105 mg, 0.2 mmol) was dissolved in
degassed DMF (8 mL). Bis(3,5-dimethylphenyl)phosphine
(1.2 g, 4.8 mmol) was added and the reaction mixture was
heated at 110 8C for 30 min. The resulting solution was
transferred via teflon tubing to the first flask. After the
addition was complete the reaction mixture was stirred at
110 8C for 3 days and then evaporated to dryness under high
vacuum at 110 150 8C. The residue was dissolved in PhMe (10
mL) and heated at 70 8C with trichlorosilane (20 mL, 198
mmol) for 4 h. Following evaporation to dryness under high
For RuCl2[(S)-HexaPHEMP][(S,S)-DPEN]: 31P{1H} NMR
(CDCl3, 162 MHz): d ˆ 45.9.
For RuCl2[(S)-HexaPHEMP][(S,S)-DACH]: 31P{1H} NMR
(CDCl3, 162 MHz): d ˆ 45.5.
For RuCl2[(S)-Xyl-HexaPHEMP][(S,S)-DPEN]: 31P{1H}
NMR (CDCl3, 162 MHz): d ˆ 44.7.
For RuCl2[(S)-Xyl-HexaPHEMP][(S,S)-DACH]: 31P{1H
NMR (CDCl3, 162 MHz): d ˆ 44.2.
For RuCl2[(S)-Xyl-HexaPHEMP][(S)-DAIPEN]: 31P{1H}
NMR (CDCl3, 162 MHz): d ˆ 42.7 (d), 46.0 (d, J ˆ 38.6 Hz).
Adv. Synth. Catal. 2003, 345, 300 307
305

Julian P. Henschke et al.
FULL PAPERS
temperature until the theoretical amount of hydrogen was
consumed. A reaction sample was diluted with acetone and
analysed by chiral GC [For acetophenone: Chirasil DEX CB,
100 oC for 7 min, then 30 oC/min to 200 oC: 9.3 min (R), 9.5 min
(S). The stereochemistry of 1-phenylethanol was assigned by
comparison with commercially available (R)-1-phenylethanol
(Aldrich). For 3'-trifluoromethylacetophenone: Chirasil DEX
CB, 100 oC for 7 min, then 15 oC/min to 200 oC: 10.6 min (R),
10.9 min (S)].
Asymmetric Hydrogenation
All hydrogenations were carried out in 50 mL Parr hydro-
genation vessels or in a Baskerville multiwelled hydrogenation
vessel equipped with injection ports with a rubber septum for
the addition of the solvent via syringe, a pressure gauge, a
tightly fitting removable internal glass liner, and a magnetic
stirring bar. Commercially available anhydrous i-PrOH (Flu-
ka) was degassed prior to use by sparging with nitrogen for at
least 30 minutes. A commercially available 1.0 M solution of t-
BuOK in t-BuOH (Aldrich) was used following degassing.
Asymmetric Hydrogenation of (E)-Ethyl b-Acetamidoc-
rotonate (11): A glass liner was charged with (E)-ethyl b-
acetamidocinnamate (1 equiv.; conducted on a 1.0 mmol scale
at S/C 100/1), the respective catalyst (as indicated in Table 1;
0.01, 0.001 or 0.0001 equiv.) and a magnetic stirrer bar. The
liner was placed in the base of a 50 mL Parr pressure vessel and
the reactor assembled, flushed with nitrogen (5 pressurisation/
release cycles, 140 psi). MeOH (to make a 0.3 M solution) was
added through the septum of the reactor via syringe. The
reactor was purged once more with nitrogen (8 pressure/
release cycles, 140 psi). The reactor was finally pressurised to
140 psi withhydrogen and stirred atroomtemperature until the
theoretical amount of hydrogen gas had been consumed. The
remaining hydrogen was then released and the solution in the
glass liner transferred to a vial. A sample was diluted with
EtOAc and the conversion and ees were determined by GC
analysis [Chirasil DEX-CB; 60 8C for 5 min, then 5 8C/min to
160 8C then 15 8C/min to 200 8C: 21.2 min (first eluting
enantiomer) and 21.8 min (second eluting enantiomer).
Asymmetric Hydrogenation of 2-methylquinoxaline (13):
The catalyst (as indicated in Table 2; 0.008 mmol) was placed in
a glass liner and the vessel assembled. This was purged with
nitrogen at least three times, by pressurising to 5 bar and
releasing the pressure. 2-Methylquinoxaline (13) (1.15 g, 8.0
mmol) was added and the reaction was purged three times with
nitrogen. A solution of t-BuOK in t-BuOH (1.0 M, 0.40 mL,
0.40 mmol) was added and the reaction was purged a further
three times with nitrogen. Finally, the vessel was pressurised to
30 bar of hydrogen and stirred at 50 8C (oil bath) for 20 h. A
sample of the product was diluted with acetone and treated
with trifluoroacetic anhydride and pyridine for several mi-
nutes. This was then analysed by GC [Chirasil DEX CB; 130 oC
for 20 min, then 10 oC/min to 200 oC, hold for 5 min: 18.2 min
(S), 18.9 min (R)] for determination of conversion and ee. The
absolute configurations of the enantiomeric products were
determined by optical rotation measurements of upgraded
(crystallised from i-PrOH) product samples prepared by
hydrogenation of 2-methylquinoxaline (13) using RuCl2[(S)-
HexaPHEMP][(S,S)-DACH] ([a]D24: ‡ 23.18 (c 1.0, EtOH))
and RuCl2[(R)-BINAP][(R)-DAIPEN] ([a]D24: À 23.18 (c 1.0,
EtOH)) (lit.[25] [a]D24: À 35.88 (c 1.0, EtOH) for (S)-2-methyl-
1,2,3,4-tetrahydroquinoxaline).
Acknowledgements
We thank Ms. Natasha Cheeseman of the Chirotech Analytical
team for her skilled technical assistance and Drs. Antonio
Zanotti-Gerosa and Ian C. Lennon for their valuable discus-
sions and help with the preparation of this manuscript.
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¡
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Asymmetric Hydrogenation of acetophenones 15a and 15b:
Standard procedure at S/C 3000/1: the catalyst (as indicated in
Table 3; 0.002 mmol) was placed in a 50 mL Parr hydrogenation
vessel. The vessel was evacuated and refilled with nitrogen
three times. A solution of the ketone (6 mmol) in anhydrous i-
PrOH (3 mL) was introduced with a syringe via the vessel
injection port and the vessel was purged with nitrogen. A 1 M
solution of t-BuOK in t-BuOH (0.1 mL, 0.1 mmol) was added
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Synthesis and Applications of HexaPHEMP, a Novel Biaryl Diphosphine Ligand
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