1,2-Bis(2,5-diphenylphospholano)methane, a new ligand for asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2007.01.018

1,2-Bis(2,5-diphenylphospholano)methane (Ph-BPM) has been prepared in good yield from 2,5-trans-diphenylphospholane-borane adduct. Rhodium and ruthenium complexes of this ligand have been prepared and their usefulness in asymmetric hydrogenation has been investigated. [Ph-BPM Rh(COD)]BF₄ showed high activity and selectivity for itaconate and dehydroamino acid hydrogenation. Ph-BPM RuCl₂(DPEN) was effective for imine hydrogenation.

Full text of DOI:10.1016/j.tetlet.2007.01.018

Tetrahedron Letters 48 (2007) 1831–1834
1,2-Bis(2,5-diphenylphospholano)methane, a new
ligand for asymmetric hydrogenation
Mark Jackson* and Ian C. Lennon
Dowpharma, Chirotech Technology Ltd, a subsidiary of The Dow Chemical Company,
Unit 162 Cambridge Science Park, Milton Road, Cambridge CB4 0GH, UK
Received 2 November 2006; revised 15 December 2006; accepted 4 January 2007
Available online 7 January 2007
Abstract—1,2-Bis(2,5-diphenylphospholano)methane (Ph-BPM) has been prepared in good yield from 2,5-trans-diphenylphospho-
lane–borane adduct. Rhodium and ruthenium complexes of this ligand have been prepared and their usefulness in asymmetric
hydrogenation has been investigated. [Ph-BPM Rh(COD)]BF4 showed high activity and selectivity for itaconate and dehydroamino
acid hydrogenation. Ph-BPM RuCl2(DPEN) was effective for imine hydrogenation.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Asymmetric hydrogenation has been readily adopted as
a method of choice to provide single enantiomer prod-
ucts by both industry and academia. Many ligands
and catalysts are now commercially available and
numerous applications have been reported.1 There is
still a need to develop new catalytic systems with
improved activity and selectivity.
activity and selectivity over the existing members of
the BPE ligand family in rhodium-catalysed asymmetric
hydrogenation.6 As a result of this we have investigated
the synthesis and applications of the methylene bridged
analogue,
1,2-bis(2,5-diphenylphospholano)methane
(Ph-BPM) 4 (Fig. 1).
A
single enantiomer of 1-hydroxy-1-oxo-2,5-trans-
Recently, a series of 1,2-bis(alkylmethylphosphino)-
methanes 1 (abbreviated as MiniPHOS, alkyl = tert-
butyl, cyclohexyl, isopropyl, phenyl) were prepared
and their use was demonstrated in the Rh(I)-catalysed
asymmetric hydrogenation of dehydroamino acids and
itaconate derivatives.2 Rh(I) complexes of these ligands
have also been used in the enantioselective hydrogena-
tion of enamides3 and (E)-b-(acylamino)acrylates.4 In
addition, Pfizer has reported a novel methylene bridged
ligand 2, which has three hindered quadrants (one of the
methyl groups of MiniPHOS has been replaced with
tert-butyl).5 This ligand is also highly effective for the
Rh(I)-catalysed asymmetric hydrogenation of dehydro-
amino acids. In general, these methylene bridged ligands
show good activity for asymmetric hydrogenation.
diphenylphospholane 5 was prepared using the literature
procedure.7 The phosphinic acid was reduced using phen-
ylsilane in toluene to give (R,R)-2,5-trans-diphenyl-
phospholane–borane adduct 6 (Scheme 1). There are a
variety of potential methods for converting compound
6 into (R,R)-Ph-BPM. Unfortunately, direct reaction
with dibromomethane was unsuccessful. The reaction
R
Me
Me
R
P
P
P
P
1a: R=tBu
1b: R=cy
1c: R=iPr
1d: R=Ph
MiniPHOS
2
Ph
Ph
Ph
We demonstrated that the ligand, 1,2-bis(2,5-diphenyl-
Ph
phospholano)ethane (Ph-BPE) 3, exhibited enhanced
P
P
P
P
Ph
4 (R,R)-Ph-BPM
Ph
Ph
Ph
3 (R,R)-Ph-BPE
Keywords: Rhodium; Asymmetric catalysis; Hydrogenation;
Phospholane.
*
Corresponding author. Tel.: +44 1223 728065; fax: +44 1223
506701; e-mail: pjackson@dow.com
Figure 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.018

1832
M. Jackson, I. C. Lennon / Tetrahedron Letters 48 (2007) 1831–1834
Ph
Ph
P
Ph
P
Ph
Ph
P
i, ii
O
i
BH3
BH3
BH3
P
P
H
OH
H
ii
Ph
H3B
Ph
Ph
Ph
Ph
9
6
5
6
iii
Scheme 1. Reagents and conditions: (i) PhSiH3, PhMe; (ii) BH3ÆMe2S
(83%).
Ph
Ph
P
P
Ph
Ph
Ph
i
BH3
BH3
P
Ph
P
OH
H
4 (
R
,
R
)-Ph-BPM
Ph
Ph
7
Scheme 3. Reagents and conditions: (i) n-BuLi, THF; (ii) 8 (12%) or 12
(61%); (iii) DABCO, PhMe (99%).
6
ii or iii
Ph
P
Ph
BH3
OR
Ph
Ph
BH3
BH3
Me
P
P
Ph
P
Ph
8 R = Ms
12 R = Tf
Ph
Ph
10
11
Scheme 2. Reagents and conditions: (i) (CH2O)n, KOH, MeOH (86%);
(ii) MsCl, DIPEA, THF (90%); (iii) Tf2O, Et3N, DCM (90%).
Figure 2.
Table 1. Hydrogenation using [(R,R)-Ph-BPM Rh(COD)]BF4
Entry
Substrate
O
S/C
Conditions
Conv. (%)
100
ee (%)
OMe
1
10,000
MeOH, 30 ꢁC, 10 bar H2, 15 min
99.5 (R)
MeO
O
2
1000
MeOH, 30 ꢁC, 10 bar H2, 6 h
100
91 (R)
+
CO2- t-BuNH3
MeO2C
AcHN
O
O
3
4
5000
5000
MeOH, 30 ꢁC, 6 bar H2, 1 h
>99
>99
>99 (S)
>99 (S)
OMe
MeOH, 30 ꢁC, 6 bar H2, 75 min
AcHN
AcHN
OH
O
5
6
3000
200
MeOH, 30 ꢁC, 10 bar H2, 18 h
>99
96%
99 (S)
OMe
Ph
Cl
Cl
MeOH, 30 ꢁC, 10 bar H2, 18 h
95 (R)
N
Boc
CO2H

M. Jackson, I. C. Lennon / Tetrahedron Letters 48 (2007) 1831–1834
Table 2. Hydrogenation using [(R,R)-Ph-BPM RuCl2(S,S)-DPEN
1833
Entry
Substrate
S/C/B
Conditions
Conv. (%)
>99
ee (%)
Ph
Ph
N
t
1
200:1:10
iPrOH, 60 ꢁC, 10 bar H2, 5 mol % KOtBu in BuOH, overnight
71
N
t
2
3
100:1:5
iPrOH, 60 ꢁC, 10 bar H2, 5 mol % KOtBu in BuOH, overnight
>99
100
82
89
MeO
MeO
t
100:1:10
iPrOH, 70 ꢁC, 10 bar H2, 10 mol % KOtBu in BuOH, overnight
N
was attempted using both borane adduct 6 and the
corresponding free phosphine.
successfully under transfer hydrogenation conditions14
and using iridium catalysis.15
The methylene bridge was introduced via hydroxy-
methylation of compound 6 using formaldehyde (Scheme
2).8 In our first approach to produce Ph-BPM, the
hydroxy group of compound 7 was converted into
mesylate 8 which was then reacted with compound 6
to give Ph-BPM borane adduct 9 (Scheme 3). Yields
were low and the reaction gave a complex mixture of
products with the only identifiable impurity being the
methylated compound 10 (Fig. 2).
1,2-Bis(2,5-diphenylphospholano)methane (Ph-BPM)
has been prepared in good yield from 2,5-trans-diphen-
ylphospholane–borane adduct. The route developed
is suitable for the large scale synthesis of this ligand.
[Ph-BPM Rh(COD)]BF4 demonstrated excellent activity
and selectivity for itaconate and dehydroamino acid
hydrogenation substrates. Work is in progress to iden-
tify new applications for this ligand and to further
extend the phenyl phospholane ligand family.
The addition of TMEDA to the lithiated diphenylphos-
pholane–borane adduct, prior to addition of the mesy-
late, resulted in an improved yield. The initial product
11 contained only one BH3. This was removed by treat-
ment with DABCO to give (R,R)-Ph-BPM 4 in 26%
overall yield for the two steps. Whilst being far from
ideal this enabled the preparation of synthetically useful
quantities of the ligand. Use of triflate 12 instead of mes-
ylate 8 resulted in a vastly improved yield of borane
adduct 9. Deprotection using DABCO in toluene gave
(R,R)-Ph-BPM 4 in near quantitative yield. This
improved method is now suitable for preparation of
multigram quantities of the ligand.9
References and notes
1. For a review describing the range of phosphorus ligands
available for asymmetric hydrogenation see: Tang, W.;
Zhang, X. Chem. Rev. 2003, 103, 3029.
2. Gridnev, I. D.; Yamanoi, Y.; Higashi, N.; Tsuruta, H.;
Yasutake, M.; Imamoto, T. Adv. Synth. Catal. 2001, 343,
118.
3. Gridnev, I. D.; Yasutake, M.; Higashi, N.; Imamoto, T.
J. Am. Chem. Soc. 2001, 123, 5268.
4. Yasutake, M.; Gridnev, I. D.; Higashi, N.; Imamoto, T.
Org. Lett. 2001, 3, 1701.
5. Hoge, G.; Wu, H.-P.; Kissel, W. S.; Pflum, D. A.; Greene,
D. J.; Bao, J. J. Am. Chem. Soc. 2004, 126, 5966.
6. Pilkington, C. J.; Zanotti-Gerosa, A. Org. Lett. 2003, 5,
1273.
7. Guillen, F.; Rivard, M.; Toffano, M.; Legros, J.-Y.;
Daran, J.-C.; Fiaud, J.-C. Tetrahedron 2002, 58, 5895.
8. For an example of this transformation see: Imamoto,
T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato, K. J.
Am. Chem. Soc. 1990, 112, 5244.
9. Borane adduct 6 (3.44 g, 13.54 mmol) was dissolved in dry
THF (30 ml) under nitrogen. The solution was cooled to
À65 ꢁC and a solution of n-BuLi (2.5 M in hexanes,
0.34 ml, 0.86 mmol) was added dropwise. After 1 h a
solution of 12 (6.20 g, 14.90 mmol) in dry THF (15 ml)
was added. The mixture was warmed to room temperature
and stirred overnight. The reaction was quenched with
1 M aqueous HCl (30 ml). The THF phase was separated
and concentrated under reduced pressure. The aqueous
phase was extracted with DCM (2 · 30 ml). The DCM
extracts were combined with the THF concentrate and
washed with water (20 ml), dried (MgSO4) and filtered
[(R,R)-Ph-BPM Rh(COD)]BF4 was prepared by reac-
tion of the ligand with [Rh(COD)2]BF4 in dichlorometh-
ane.10 Good activity and selectivity was shown for a
number of common substrates, including dimethyl itac-
onate, methyl acetamidoacrylate, acetamidoacrylic acid
and methyl acetamidocinnamate (Table 1).11 The pre-
catalyst (R,R)-Ph-BPM RuCl2(S,S)-DPEN was pre-
pared for use in imine hydrogenation (Table 2).12
(R,R)-Ph-BPM RuCl2(R,R)-DPEN was also prepared
but showed inferior selectivity. N-(1-Phenylethylid-
ene)aniline was hydrogenated with moderate selectivity,
alternative catalysts for this substrate have been
reported.13 N-(1-Phenylethylidene)benzylamine was
hydrogenated with good selectivity, comparable with
the best literature results.14 1-Methyl-6,7-dimethoxy-
3,4-dihydroisoquinoline was hydrogenated with good
selectivity. This substrate has also been hydrogenated

1834
M. Jackson, I. C. Lennon / Tetrahedron Letters 48 (2007) 1831–1834
through silica (25 g) eluting with DCM (50 ml). The
128.3, 127.8, 127.4, 100.2, 99.7, 49.5, 47.3, 39.8 (t, J
20 Hz), 31.2, 30.6, 30.1 and 28.4; 31P NMR (162 MHz,
CDCl3) d ppm À6.9 (d, J 136 Hz).
solution was concentrated under reduced pressure and the
residue crystallised from ethyl acetate/heptane (1:3, 16 ml)
to give 9 (4.33 g, 61%). Borane adduct 9 (986 mg,
1.90 mmol) and DABCO (639 mg, 5.69 mmol) were
charged to a 50 ml Schlenk flask. The flask was deoxy-
genated by evacuation and filling with nitrogen (·5).
Toluene (10 ml) was added and the solution was heated at
60 ꢁC for 2 h. The solution was allowed to cool to room
temperature with stirring overnight. The reaction mixture
was filtered through a pad of silica (6 g) under nitrogen,
eluting with toluene (20 ml). The solvent was evaporated
under reduced pressure to give (R,R)-Ph-BPM 4 (929 mg,
99%), 1H NMR (400 MHz, CDCl3) d ppm 7.25–6.90 (20H,
m), 3.60–3.50 (2H, m), 3.27–3.18 (2H, m), 2.36–2.24 (2H,
m), 2.16–2.06 (2H, m), 1.94–1.70 (4H, m) and 0.68 (2H,
m); 13C NMR (100 MHz, CDCl3) d ppm 144.4 (t, J 8 Hz),
139.1, 128.7, 128.6, 128.3 (t, J 5 Hz), 128.1, 126.2, 125.8,
49.3 (t, J 5 Hz), 47.3 (t, J 5 Hz), 36.9, 31.8 and 22.0 (t, J
34 Hz); 31P NMR (162 MHz, CDCl3) d ppm 4.5. Found
HRMS m/z [M+H]+, 493.220, C33H35P2 requires
493.2214.
11. Representative procedure: The reaction was carried out in
an Argonaut Endeavor hydrogenation vessel. The glass
liner was charged with dimethyl itaconate (1.58 g,
10.0 mmol) and [(R,R)-Ph-BPM Rh(COD)]BF4 (0.8 mg,
0.001 mmol, S/C 10,000). The vessel was charged to 10 bar
nitrogen and vented (·5). Degassed methanol (4 ml) was
added. The vessel was charged to 10 bar nitrogen and
vented (·2). The reaction was stirred at 1000 rpm and
heated to 30 ꢁC. The vessel was charged to 10 bar
hydrogen. Hydrogen uptake was complete after 15 min.
The mixture was cooled to room temperature, vented and
evaporated to give (R)-2-methylsuccinic acid dimethyl
ester, conversion 100%, ee 99.5% (Chiraldex GTA,
30 m · 0.25 mm, injector/detector 180 ꢁC, helium 14 psi,
90 ꢁC for 6 min, then ramp at 1 ꢁC/min to 105 ꢁC,
retention times S 9.81 min, R 10.03 min).
12. For method of preparation see: Ohkuma, T.; Koizumi,
M.; Doucet, H.; Pham, T.; Kozawa, M.; Murata, K.;
Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1998, 120, 13529.
13. For an example of this reaction see: Cobley, C. J.;
Henschke, J. P. Adv. Synth. Catal. 2003, 345, 195.
14. Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916.
10. Data for [(R,R)-Ph-BPM Rh(COD)]BF4: 1H NMR
(400 MHz, CDCl3) d ppm 7.62–7.55 (8H, m), 7.47–7.40
(2H, m), 7.20–7.15 (6H, m), 6.81 (4H, d, J 8 Hz), 5.30 (2H,
m), 3.70–3.60 (4H, m), 3.32–3.26 (2H, m), 3.15–2.98 (2H,
m), 2.52–2.38 (6H, m), 2.25–2.15 (2H, m), 2.08–1.96 (4H,
m), 1.70–1.60 (2H, m) and 1.38–1.28 (2H, m); 13C NMR
(100 MHz, CDCl3) d ppm 140.4, 135.3, 129.9, 129.4, 129.1,
15. Morimoto, T.; Achiwa, K. Tetrahedron: Asymmetry 1995,
6, 2661.