Synthesis of a new water-soluble C2-symmetric chiral diamine: Preliminary investigation of its catalytic properties for asymmetric hydrogenation under biphasic conditions

Article abstract of DOI:10.1021/jo020506v

A water-soluble version of N,N′-dimethyl-1,2-diphenylethane-1,2-diamine was prepared by introduction of phosphonic acid moieties on the para position of the aromatic rings. Preliminary investigation of the catalytic properties of the iridium complex of this ligand under biphasic conditions showed that this system compared well with the homogeneous counterpart for the asymmetric hydrogenation of ketones but with noticeably higher reaction rates for the biphasic system.

Full text of DOI:10.1021/jo020506v

Syn th esis of a New Wa ter -Solu ble C2-Sym m etr ic Ch ir a l Dia m in e:
P r elim in a r y In vestiga tion of Its Ca ta lytic P r op er ties for
Asym m etr ic Hyd r ogen a tion u n d er Bip h a sic Con d ition s
Ce´line Maillet,† Thoniyot Praveen,† Pascal J anvier,† Se´bastien Minguet,‡ Michel Evain,§
Christine Saluzzo,| M. Lorraine Tommasino,| and Bruno Bujoli*,†
Laboratoire de Synthe`se Organique, UMR CNRS 6513, 2 Rue de la Houssinie`re, BP92208,
44322 Nantes Cedex 03, France, Laboratoire de Chimie, Electrochimie Mole´culaires et Chimie Analytique,
UMR CNRS 6521, Faculte´ des Sciences et des Techniques, 6 Avenue V. Le Gorgeu, BP 809,
29285 Brest Cedex, France, Institut des Mate´riaux J ean Rouxel, UMR CNRS 6502,
2 Rue de la Houssinie`re, BP92208, 44322 Nantes Cedex 03, France, Laboratoire de Catalyse et Synthe`se
Organique, UMR CNRS 5622, UCBL, CPE, Baˆt 308, 43 Boulevard du 11 Novembre 1918,
69622 Villeurbanne Cedex, France
bruno.bujoli@chimie.univ-nantes.fr
Received August 1, 2002
A water-soluble version of N,N′-dimethyl-1,2-diphenylethane-1,2-diamine was prepared by introduc-
tion of phosphonic acid moieties on the para position of the aromatic rings. Preliminary investigation
of the catalytic properties of the iridium complex of this ligand under biphasic conditions showed
that this system compared well with the homogeneous counterpart for the asymmetric hydrogenation
of ketones but with noticeably higher reaction rates for the biphasic system.
In tr od u ction
others have shown that in the case of phosphines3a-c,e-h
or diamines3d functionalized by PO3Na2 moieties, soft
metals such as PdII, RhI, RuII, or IrI preferably bind to
the phosphine or nitrogen centers, thus opening the way
to their potential use in biphasic catalysis. This approach
was successfully developed by us with new iridium and
rhodium bisphosphonato-2,2′-bipyridine complexes, ef-
ficient for the hydrogenation of substituted acetophe-
nones in water under hydrogen pressure.3d Encouraged
by these good results, and as a logical extension of this
work, we were interested in knowing if this methodology
might be applicable to chiral series. For this purpose, we
describe in this paper a water-soluble version of enan-
tiomerically pure (1R,2R)- and (1S,2S)-N,N′-dimethyl-1,2-
diphenylethane-1,2-diamines 2a , functionalized by phos-
phonic acid units on the phenyl rings. The corresponding
iridium complexes were tested for the asymmetric hy-
drogenation of various aromatic ketones under hydrogen
pressure in a water-methanol mixture. The following
justified this choice: (i) the facile large-scale preparation
of C2-symmetric diamine 2a reported in the literature5
that should be easy to transpose to parent functionalized
The use of water-soluble organometallic catalysts for
chemical reactions is one successful solution to the major
problem of homogeneous catalysis, i.e., the expensive
separation of catalyst from products and possible uncon-
verted reactants. The best evidence is given by the
variety of large-scale industrial processes parallel to
academic research.1 Aqueous two-phase catalysis is
located between heterogeneous and homogeneous cataly-
sis, and in this context, there is a steady demand for
water-soluble and water-stable metal complexes. Despite
the broad range of polar groups employed to achieve
water solubility, sulfonated derivatives have proven to
be the most efficient, as illustrated by the famous tris-
(m-sulfonatophenyl)phosphine2 associated to rhodium for
biphasic aqueous hydroformylation or hydrogenation.
Very close in nature to sulfonate is the phosphonate PO3-
Na2 group that can also confer an outstanding solubility
in water. Curiously, however, the use of these polar units
to prepare water-soluble ligands is rather limited in the
literature,3 probably because of the well-known ability
of phosphonic acids to strongly coordinate most of the
metals at various oxidation states.4 However, we and
(3) (a) Schull, T. L.; Fettinger, J . C.; Knight, D. A. J . Chem. Soc.,
Chem. Commun. 1995, 1487-1488. (b) Schull, T. L.; Fettinger, J . C.;
Knight, D. A. Inorg. Chem. 1996, 35, 6717-6723. (c) Lelie`vre, S.;
Mercier, F.; Mathey, F. J . Org. Chem. 1996, 61, 3531-3533. (d)
Penicaud, V.; Maillet, C.; J anvier, P.; Pipelier, M.; Bujoli, B. Eur. J .
Org. Chem. 1999, 1745-1748. (e) Dressick, W. J .; George, C.; Brandow,
S. L.; Schull, T. L.; Knight, A. J . Org. Chem. 2000, 65, 5059-5062. (f)
Kant, M.; Bischoff, S.; Siefken, R.; Gru¨ndemann, E.; Ko¨ckritz, A. Eur.
J . Org. Chem. 2001, 477-481. (g) Bischoff, S.; Kant, M. Catal. Today
2001, 66, 183-189. (h) Ko¨ckritz, A.; Bischoff, S.; Kant, M.; Siefken, R.
J . Mol. Catal. A: Chem. 2001, 174, 119-126.
† UMR CNRS 6513.
‡ UMR CNRS 6521.
§ UMR CNRS 6502.
| UMR CNRS 5622.
(1) For a detailed review, see: (a) Aqueous Phase Organometallic
Catalysis: Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim,
Germany, 1998. (b) Cornils, B.; Herrmann, W. A.; Eckl, R. W. J . Mol.
Catal. A: Chem. 1997, 116, 27-33.
(2) See, for example: (a) Rhoˆne-Poulenc Recherche (Kuntz, E.). FR
Patent 2.314.910, 1975. Kuntz, E. G. Chem. Technol. 1987, 570-575.
(b) Sheldon, R. A. C. R. Acad. Sci. Paris, Se´rie IIc, Chem. 2000, 3, 541-
551. (c) Grosselin, J . M.; Mercier, C.; Grass, F. Organometallics 1991,
10, 2126-2133.
(4) See, for example: Clearfield, A. In Progress in Inorganic
Chemistry Karlin, K. D., Ed.; Wiley & Sons: New York, 1998; pp 371-
510.
10.1021/jo020506v CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/25/2002
J . Org. Chem. 2002, 67, 8191-8196
8191

Maillet et al.
SCHEME 1a
a
Reaction conditions: (i) aqueous CH3NH2 (96%). (ii) (a) Zinc/Me3SiCl, THF; (b) DL-tartaric acid, 95% EtOH (63%). (iii) SiO2
chromatography eluting with EtOH/Et2O saturated with NH3 (1/9) (80%). (iv) L- or D-tartaric acid, 95% EtOH (85% for d-2b; 90% for
l-2b). (v) Acetaldehyde, Et2O, 4 Å MS (97.5%). (vi) Pd2dba3, HP(O)(OEt)2, Et3N, Ph3, toluene, 105 °C (81%). (vii) Me3SiBr, CH2Cl2, then
MeOH (81%).
diamines; (ii) beside phosphines that have proved to be
highly efficient ligands for asymmetric catalysis,6a,b ni-
trogen-based ligands are also good candidates in this field
and offer several advantages such as air stability and
ease of preparation and handling;6c (iii) iridium complexes
of diamine 2a have been reported for the asymmetric
in our case, to the formation of large amounts of 4-bro-
mobenzylmethylamine. The separation of the d,l-2b and
meso-2b isomers by crystallization in various solvents or
by treatment of the crude mixture with racemic tartaric
acid in ethanol failed, but the latter treatment was
efficient for isolation of the pure mixture of the d,l and
meso compounds, the separation of which was then easily
performed by chromatography on silica eluting with
ethanol gradients in diethyl ether saturated with am-
monia.8 Then, the resolution of the d,l diamine 2b was
carried out using L-(+)-tartaric acid and D-(-)-tartaric
acid successively, according to an optimized protocol
derived from Alexakis et al.,5 to give the (R,R)- and (S,S)-
diamines in good yields. At this stage, the introduction
of the phosphonate groups was investigated via a Pd-
catalyzed cross-coupling reaction of the bromoaryl units
and diethyl phosphite, as described by Hirao et al.9 Very
poor results were obtained using the standard conditions,
probably because of the ability of the diamine to coordi-
nate palladium. This problem was overcome by using a
large excess of triphenylphosphine (10-fold excess with
respect to the diamine) as previously reported by us10 for
a similar reaction in the case of bipyridines. Moreover,
cleaner reactions were observed when Pd((P(C6H5)3)4 was
replaced by Pd2dba3 as the palladium(0) source. Never-
theless, under our best conditions, the yield did not
reduction
of
R-keto-
esters with molecular hydrogen with ee values up to
72%,7a and the rhodium analogue performed the reduc-
tion of acetophenone under hydride transfer conditions
with 67% ee (KOH/i-PrOH) and 56% ee (tBuOK/i-
PrOH).7b
Resu lts a n d Discu ssion
The desired chiral bisphosphonato diamine 2c (Scheme
1) was prepared starting from the enantiomerically pure
d and l forms of C2-symmetric diamine 2b synthesized
by adapting the procedure described by Alexakis et al.5
for the preparation of N,N′-dimethyl-1,2-diphenylethane-
1,2-diamine 2a . Imine 1 was prepared by condensation
of 4-bromobenzaldehyde with an aqueous solution of
methylamine. The reductive dimerization of 1 on a 0.25
mol scale using the combination of zinc and chlorotri-
methylsilane afforded the mixture of racemic d,l and
meso diamines 2b in a 1:1 ratio. In our hands, THF was
found to be the best solvent compared to acetonitrile,
which is usually recommended in the literature but led,
(8) For very large-scale preparations, a limiting step is the separa-
tion of meso-2b and d,l-2b by column chromatography. To overcome
this problem, this mixture can be treated by acetaldehyde to form
meso-3 and d,l-3. The aminal d,l-3 was selectively crystallized out of
acetonitrile, and after hydrolysis under acidic conditions, d,l-2b was
recovered and used for the separation of the d and l isomers (yield of
d,l-2b isolated from a meso-2b and d,l-2b mixture on a 30 g scale:
79%). See Supporting Information.
(9) Hirao, T.; Masunage, T.; Yoshiro, O.; Agawa, T. Synthesis 1981,
56-57.
(10) Penicaud, V.; Odobel, F.; Bujoli, B. Tetrahedron Lett. 1998, 39,
3689-3692.
(5) Alexakis, A.; Aujard, I.; Kanger, T.; Mangeney, P. Org. Synth.
1999, 76, 23-36.
(6) (a) Noyori, R. In Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Noyori, R.; Ohkuma, T. Angew. Chem.,
Int. Ed. 2001, 40, 40-73. (c) Fache, F.; Schulz, E.; Tommasino, M. L.;
Lemaire, M. Chem. Rev. 2000, 100, 2159-2231.
(7) (a) Tommasino, M. L.; Thomazeau, C.; Touchard, F.; Lemaire,
M. Tetrahedron: Asymmetry 1999, 10, 1813-1819. (b) Bernard, M.;
Guiral, V.; Delbecq, F.; Fache, F.; Sautet, P.; Lemaire, M. J . Am. Chem.
Soc. 1998, 120, 1441-1446.
8192 J . Org. Chem., Vol. 67, No. 23, 2002

New Water-Soluble C2-Symmetric Chiral Diamine
TABLE 1. Exp er im en ta l Da ta for th e Asym m etr ic Hyd r ogen a tion of Acetop h en on e u n d er H 2 P r essu r e Usin g Liga n d 2b
in Meth a n ol a n d Liga n d 2c in 1/1 Wa ter /Meth a n ola
entry
conditions
metal/ligand/substrate
alcohol yield (%)
eef (%)
1b
2b
3b
4b
(R,R)-2b + [Ir(COD)Cl]2
(R,R)-2b + [Ir(COD)2]BF4
(R,R)-2c + [Ir(COD)2]BF4
(R,R)-2c + [Ir(COD)2]BF4
(R,R)-2c + [Ir(COD)2]BF4
(R,R)-2c + [Ir(COD)2]BF4
(R,R)-2c + [Ir(COD)2]BF4
(R,R)-2c + [Ir(COD)2]BF4
(R,R)-2c + [Ir(COD)2]BF4
(R,R)-2c + [Ir(COD)2]BF4
(R,R)-2c + [Ir(COD)2]BF4
(R,R)-2c + [Ir(COD)2]BF4
(R,R)-2c + [Rh(COD)2]BF4
(R,R)-2c + [Ru(p-cym.)(Cl)2]2
1/2/40
1/2/40
1/2/40
31
>99
93
58
60
55
47
34
50
54
52
51
52
53
50
1/2/200
1/2/200
1/2/200
1/2/200
1/2/200
1/2/200
1/2/1000
1/2/1000
1/1/200
1/2/200
1/2/200
28
5b,c
>99
>99
>99
>99
>99
38
6d cycle 1
7d cycle 2
8d cycle 3
9d cycle 4
10d
11d,e
>99
15
12d
13d
formation of Rh metal
37
14d
16
a
b
General conditions: [Ir, Rh, or Ru] ) 2 × 10-3 M, 1/2/10 metal/ligand/NaOH, 45 atm, 50 °C, 21 h. Catalyst prepared under air.
c OH- (6 equiv) added with respect to iridium. Catalyst prepared under argon. e Reaction time: 62 h. f (S)-Enantiomer. Enantiomeric
excesses were measured either by GC on a Machery-Nagel LIPODEX E column (length, 25 m; diameter, 250 µ; flow, 2 mL/mn; carrier
gas, helium; 86 °C isotherm) or by HPLC on a Chiracel OD-H column (eluent, 98/2 hexane/i-PrOH; flow, 0.5 mL/min; pressure, 14 atm)
with similar results.
d
exceed 70% of a mixture of the desired bisphosphonate
diamine contaminated with its monofunctionalized ana-
logue. Protection of the diamine was thus necessary, and
for this purpose, the two enantiomers of 2b were easily
converted into the corresponding d and l aminals 3 by
reaction with acetaldehyde. An X-ray crystallographic
study clearly indicates that the d form of 3 corresponds
to the (R,R)-enantiomer. On substrate 3, the palladium-
catalyzed phosphonation of the aryl rings proceeded well.
In the workup of the reaction, the major part of the
triphenylphosphine was recovered by crystallization and
an acid treatment step was introduced, allowing the
removal of the aminal protecting group. The phosphonate
ester form of diamines d- and l-2c was thus obtained in
good yields, and the corresponding phosphonic acid
analogues were obtained by their deprotection using Mc
Kenna’s method.11
Preliminary experiments were then run for the evalu-
ation of the catalytic properties of aqueous solutions of
2c for the asymmetric reduction of ketones (i) under
hydrogen pressure and (ii) under hydride transfer condi-
tions. Two homogeneous catalytic runs in methanol were
first performed under H2 pressure (45 atm, 50 °C, 21 h)
using ligand 2b treated with two iridium sources: [Ir-
(COD)Cl]2 and [Ir(COD)2]BF4 (Ir/acetophenone molar
ratio ) 2.5%). Comparable ee values (∼58%) were
obtained, with a significantly higher reaction rate for the
cationic complex (Table 1, entries 1 and 2), and hence
the fluoroborate salt was chosen to study the catalytic
properties of 2c under biphasic conditions. Ligand 2c was
soluble in water after addition of 5 equiv of sodium
hydroxide. Due to the very poor solubility of [Ir(COD)2]-
BF4 in water, a cosolvent had to be added. Consequently,
the iridium precursor was first dissolved in methanol and
the resulting solution was mixed with the same volume
of ligand 2c in water as prepared above. The mixture was
stirred at ambient temperature for 4 days; at shorter
times, some problems of stability were observed, with the
formation of a small amount of black precipitate, result-
ing in a pollution of the reactor as evidenced by blank
experiments that were not correct after a catalytic run.
Under the former conditions, ligand 2c compared fairly
well with the homogeneous system (entry 3 versus entry
2). Attempts to run tests in pure water (by evaporation
of the complex prepared in a water/methanol mixture and
redissolution in water) resulted in lower ees (∼35%).
Whereas a lower iridium/substrate loading (0.5%) led
to low conversion in 21 h (entry 4), the addition of sodium
hydroxide in the reaction medium allowed higher reac-
tion rates but with a decrease of the enantioselectivity
(entry 5). A significant ee improvement was achieved by
preparing the complex under an inert atmosphere since
a quantitative yield and stable ees (average ca. 52%) were
observed in a recycling experiment (entries 6-9). Comple-
tion of the reduction with similar ees was also obtained
even with a further decrease of the catalyst loading
(0.1%), although a longer reaction time was required
(entries 10 and 11). A decrease of the ligand/iridium ratio
slowed the reaction rate (entry 12), while attempts to use
rhodium or ruthenium instead of iridium resulted in an
unstable catalyst in the former case and lower conversion
and ee in the latter case (entries 13 and 14).
The biphasic system was then tested for the reduction
of other ketones, leading to ee values somewhat lower
than those recorded with the homogeneous system based
on 2b (Table 2, entries 1-4) but showing higher yields.
The validity of these data was confirmed (i) by repeat-
ing the test corresponding to entry 3 satisfactorily and
(ii) by measuring the initial reaction rates for the
homogeneous system 2b (TOF ≈ 10 h-1; ee 75%) and the
biphasic system 2c (TOF ≈ 19 h-1; ee 71%), used for the
hydrogenation of 2-methoxyacetophenone (Ir/substrate )
0.1%). Interestingly, a significantly higher reaction rate
was observed with diamine 2c, consistent with data from
entry 2. It is also worth noting that in the case of the
bulky tert-butylphenyl ketone (entry 4), (i) the opposite
enantiomers of 2,2-dimethyl-1-phenyl-1-propanol were
formed using ligand 2b versus 2c and (ii) better results
were obtained compared to the Ru-[(S)-BINAP/(S,S)-
(11) McKenna, C. E.; Higa, M. T.; Cheung, N. H., McKenna, M. C.
Tetrahedron Lett. 1977, 155-158.
J . Org. Chem, Vol. 67, No. 23, 2002 8193

Maillet et al.
TABLE 2. Com p a r ed Va lu es for th e Asym m etr ic Hyd r ogen a tion of Va r iou s Keton es u n d er H 2 P r essu r e, Usin g Liga n d
(S,S)-2b in Meth a n ol a n d Liga n d (S,S)-2c in 1/1 Wa ter /Meth a n ola
a
General conditions: [Ir] ) 2 × 10-3 M, 1/2/10 Ir/ligand/NaOH, 45 atm, 50 °C, 21 h, Ir/substrate ) 0.5%. Catalyst: (S,S)-2c +
[Ir(COD)2]BF4 in 1/1 MeOH/water prepared under argon.
DPEN] system for which the substrate was surprisingly
almost inert (6% yield, 61% ee even under 50 atm of H2).6b
The case of 4-methylcyclohexanone was also examined,
to compare the cis/trans ratios of the corresponding
alcohol formed in biphasic (using 2c) and homogeneous
conditions (using 2b). Similar results were obtained
(conversion > 99%; cis/trans ≈ 25/75), but in the latter
case, the final product was contaminated by 15% of 1,1-
dimethoxy-4-methylcyclohexane.
It was also of interest to study the ability of ligand 2c
complexed to rhodium [precursor: [Rh(COD)Cl]2] to cata-
lyze asymmetric transfer hydrogenation in conditions
similar to those described by Thorpe et al.12 [t-BuOK, 1:1
water/i-PrOH] with water soluble aminosulfonamide
ligands. The activity of our system for the reduction of
acetophenone (46% ee for a 95% yield) was found to be
similar to that reported with 2a in homogeneous condi-
tions (46% ee for a 98% yield),13 using comparable
experimental conditions (1:2:4:20 Rh/ligand/t-BuOK/
substrate).
sulfonates, for the derivatization of homogeneous ligands
to be used in aqueous media. Our future work will
concentrate on the development of a supported version
ligand 2c that will be readily accessible, taking account
of our successful experience using bipyridine-bisphos-
phonates.14
Exp er im en ta l Section
Chemical analyses were performed by the C.N.R.S. Analysis
Laboratory (Vernaison). The optical purity of compound 2b was
determined by HPLC analyses using a Chiracel OD-H column
(flow ) 0.5 mL/min, solvent ) 95/5 hexane/i-propanol, detec-
tion ) 254 nm, retention times: meso, 5.4 min; d, 6.7 min; l,
9.5 min).
X-ray crystal data for d-3 (Figure 1): C18H20Br2N2; M )
424.2, monoclinic space group C2 (No. 5), T ) 100 K, Fcalcd
)
1.593 g/cm3, Z ) 4, a ) 22.9874(5) Å, b ) 5.16190(10) Å, c )
15.9750(4) Å, â ) 111.1200(10)°, V ) 1768.24(7) Å3, µ ) 2.291
mm-1. Final R [F2 > 2σ(F2)] ) 0.0345, wR(F2) ) 0.0997 for
229 variables and 4896 data points. Full details can be found
in Supporting Information.
N-Meth yl-4-br om oben zim in e (1). 4-Bromobenzaldehyde
(48 g, 0.26 mol) was added to an aqueous solution (40% w/w,
26 mL) of methylamine cooled to 0 °C. The resulting milky
white emulsion was stirred at room temperature for 1 h. The
crude mixture was then extracted with 150 mL of dichlo-
romethane. The organic phase was separated, washed with
100 mL of water, dried over sodium sulfate, and filtered, and
the solvent was evaporated under reduced pressure. The
desired imine was obtained as a white solid (49.3 g) in 96%
yield. 1H NMR (200 MHz, CDCl3): δ 3.50 (3H, d, 4J ) 1.7 Hz),
7.55 (4H, m), 8.22 (1H, q, 4J ) 1.7 Hz). 13C NMR (50 MHz,
CDCl3): δ 48.2, 124.9-129.3-131.8-135.1, 161.2.
In conclusion, this work gives evidence that organo-
metallic complexes functionalized by PO3H2 moieties can
be advantageously used in biphasic catalytic processes,
with an easy recovery of the metal complex in the
aqueous phase. This is the first example of chiral nitrogen
ligand derivatized using this strategy. The preliminary
catalytic results show that the reported diamine-bispho-
sphonate 2c allows the asymmetric reduction of ketones
under hydrogen pressure or under hydride transfer
conditions as well, with performances very close, or in
some cases superior, to that observed with the homoge-
neous parent system using 2b. As a consequence, phos-
phonates appears to be a valuable option, parallel to
m eso- a n d d ,l-1,2-Bis-(4-br om op h en yl)-N,N′-d im eth yl-
eth a n e-1,2-d ia m in e (2b). Zinc (325 mesh, 16.5 g, 0.25 mol)
was suspended in anhydrous freshly distilled THF (75 mL)
under argon. The zinc powder was activated by addition of 1,2-
(12) Thorpe, T.; Blacker, J .; Brown, S. M.; Bubert, C.; Crosby, J .;
Fitzjohn, S.; Muxworthy, J . P.; Williams, J . M. J . Tetrahedron Lett.
2001, 42, 4041-4043.
(13) Touchard, F.; Bernard, M.; Fache, F.; Lemaire, M. J . Mol. Catal.
A: Chem. 1999, 140, 1-11.
(14) (a) Maillet, C.; J anvier, P.; Pipelier, M.; Praveen, T.; Andres,
Y.; Bujoli, B. Chem. Mater. 2001, 13, 2879-2884. (b) Maillet, C.;
J anvier, P.; Bertrand, M.; Praveen, T.; Bujoli, B. Eur. J . Org. Chem.
2002, 1685-1689.
8194 J . Org. Chem., Vol. 67, No. 23, 2002

New Water-Soluble C2-Symmetric Chiral Diamine
dibromoethane (2.2 mL) using a syringe while stirring, and
the mixture was heated under mild reflux for 1 min. After the
mixture was cooled to room temperature, chlorotrimethylsilane
(4.5 mL) was added with a syringe and evolution of ethylene
gas was observed. The reaction medium was stirred for 45 min,
and the imine 1 (49.3 g in 150 mL of dry THF, 0.25 mol) was
added in one portion. Chlorotrimethylsilane (48 mL, 0.38 mol)
was then added dropwise over a 30 min period, while keeping
the flask in an oil bath warmed at 35 °C. The mixture was
then refluxed for 3 h and cooled to 0 °C. Under strong stirring,
a solution prepared by mixing concentrated aqueous am-
monium hydroxide (75 mL) and saturated aqueous ammonium
chloride (225 mL) was carefully poured into the flask; after
45 min, the remaining zinc was removed by filtration over
Celite. The organic layer was separated and the aqueous phase
extracted with dichloromethane (3 × 300 mL). The combined
organic phases were dried over sodium sulfate and evaporated
after filtration to give an orange deliquescent residue. Ethanol
(95%) was added (270 mL), and the crude mixture was
refluxed, resulting in a clear yellow solution. Meanwhile,
racemic tartaric acid (18.5 g, 0.123 mol) was dissolved in 95%
hot ethanol (150 mL) and added to the clear diamine solution,
and the resulting mixture was refluxed for 1 h. It was allowed
to cool at room temperature and allowed to stand overnight.
The precipitate formed was collected by filtration and washed
with cold 95% ethanol (3 × 50 mL). This salt (72.5 g) was
suspended in 445 mL of distilled water, and 37 mL of aqueous
50% (w/w) sodium hydroxide was added, followed by 370 mL
of dichloromethane. After stirring for 1 h, the phases were
separated and the aqueous phase was extracted using dichlo-
romethane (3 × 230 mL). The combined organic phases were
washed with 460 mL of saturated NaCl aqueous solution, dried
over sodium sulfate, and evaporated to give the pure diamine
2b (white powder, 31 g, 63% yield) as a 50/50 mixture of the
meso and d,l isomers. The meso compound was isolated by
column chromatography (SiO2), eluting with diethyl ether
saturated with ammonia, and then the d,l mixture was
recovered eluting with EtOH/Et2O saturated with NH3 (1/9)
with an 80% separation yield. meso-2b 1H NMR (200 MHz,
CDCl3): δ 1.43 (2H, s), 2.11 (6H, s), 3.56 (2H, s), 7.11 (4H, d,
3J ) 8.4 Hz), 7.45 (4H, d, 3J ) 8.4 Hz). 13C NMR (50 MHz,
CDCl3): δ 34.5, 70.1, 121.5-130.1-131.6-139.4. mp: 140 °C.
d,l-2b 1H NMR (200 MHz, CDCl3): δ 1.88 (2H, s), 2.22 (6H,
combined organic phases were washed with 70 mL of saturated
NaCl aqueous solution, dried over sodium sulfate, and evapo-
rated. The resulting crude mixture (ee 67%) was treated once
with D-tartaric acid, using a procedure identical to that
described for the preparation of the d diamine 2b. The l
diamine 2b (5.25 g, ee ) 99%; yield of the separation ) 90%)
20
was finally obtained as a white deliquescent powder. [R]D
-84.5 (c 1, CH2Cl2). Anal. Calcd for C16H18N2Br2: C, 48.26;
H, 4.56; N, 7.04. Found: C, 47.93; H, 4.58; N, 6.98.
d - a n d l-4,5-Bis-(4-br om op h en yl)-1,2,3-tr im eth ylim i-
d a zolid in e (3). The desired d or l diamine 2b (4.38 g, 0.011
mol), 58 mL of dry diethyl ether, 4 Å molecular sieves (4.2 g),
and acetaldehyde (1.22 mL, 0.022 mol) were charged in a flask,
under argon. The mixture was stirred for 1.5 h, filtered, and
evaporated to yield 3 as a white powder (4.54 g, 97.5% yield),
which was crystallized from acetonitrile as colorless needles.
3
1H NMR (200 MHz, CDCl3): δ 1.31 (3H, d, J ) 5.8 Hz), 2.20
3
3
(3H, s), 2.24 (3H, s), 3.24 (1H, d, J ) 8.6 Hz), 3.50 (1H, d, J
) 8.6 Hz), 3.90 (1H, q, 3J ) 5.8 Hz), 7.0 (4H, m), 7.37 (4H, m).
13C NMR (50 MHz, CDCl3): δ 17.0, 35.5, 38.3, 76.3, 77.9, 80.8,
121.3-129.8-131.4-138.7-139.0. l-(3) [R]D20 -97.7 (c 1, CH2-
20
Cl2). Mp: 115 °C. d-3: [R]D 97.7 (c 1, CH2Cl2). Mp: 115 °C.
Anal. Calcd for C18H20N2Br2: Br, 37.67; C, 50.96; H, 4.75; N,
6.60. Found: Br, 37.69; C, 51.01; H, 4.81; N, 6.63.
d - a n d l-1,2-Bis-(4-d ih yd r oxyp h osp h or ylp h en yl)-N,N′-
d im eth yl-eth a n e-1,2-d ia m in e (2c). Aminal 3 (0.5 g, 1.18
mmol), triphenylphosphine (3.09 g, 11.8 mmol), and Pd2(dba)3
(0.109 g, 0.118 mmol) were charged in a flask under argon.
Toluene (14 mL), triethylamine (0.72 mL, 5.18 mmol), and
diethyl phosphite (0.67 mL, 5.18 mmol) were added, and the
mixture was degassed thoroughly using several vacuum/argon
cycles. The reaction medium was stirred and heated at 102-
105 °C for 15 h. After the mixture was cooled to room
temperature, water (20 mL) and dichloromethane (20 mL)
were added and the aqueous layer was extracted with dichlo-
romethane (2 × 4 mL). The combined organic extracts were
washed with water (2 × 10 mL) and brine, dried over sodium
sulfate, and evaporated under vacuum to obtain a yellow
gummy mass. To this residue was added boiling 95% ethanol
(15 mL) until complete dissolution, and the mixture was
allowed to stand at room temperature for 1 h. The crystalline
triphenylphosphine thus formed was filtered off (1.9 g), and
the mother liquor was evaporated under reduced pressure. The
crude product was dissolved in a mixture of methanol (8 mL)
and dichloromethane (6 mL), and 12 M HCl (0.5 mL) was
added. After stirring for 2 h, the solution was evaporated under
vacuum and water (20 mL) and dichloromethane (20 mL) were
added. The organic layer was extracted with water (2 × 4 mL),
and the combined aqueous layers were washed with dichlo-
romethane (6 × 10 mL). The resulting turbid aqueous phase
was neutralized using a saturated sodium bicarbonate solution
(pH 7-8) and then extracted with 20 mL of dichloromethane.
The aqueous layer was further washed with dichloromethane
(3 × 3 mL), and the combined organic extracts were washed
with water (15 mL) and brine, dried using sodium sulfate, and
evaporated to dryness to give the ester form of diamine 2c as
a colorless oil (0.43 g, yield 81%), which was used directly for
the hydrolysis of the ester groups. If performed on a larger
scale (2.3 g of starting 3), the yield of this synthesis was about
3
3
s), 3.44 (2H, s), 6.88 (4H, d, J ) 8.4 Hz), 7.30 (4H, d, J ) 8.4
Hz). 13C NMR (50 MHz, CDCl3): δ 34.5, 70.5, 120.9-129.7-
131.2-139.8. Mp: 118 °C.
d- an d l-1,2-Bis-(4-br om oph en yl)-N,N′-dim eth yl-eth an e-
1,2-d ia m in e (2b). A mixture of pure d,l diamine 2b (11.7 g,
0.0295 mol) and 257 mL of 95% ethanol was refluxed until
the diamine dissolved. Meanwhile, 4.41 g of L-tartaric acid
(0.0294 mol) was dissolved in boiling 95% ethanol (257 mL)
and added to the diamine solution, and the resulting mixture
was refluxed for 1 h, after the observation of salt formation.
The reaction medium was allowed to cool to room temperature
for 2 h, and the precipitate was collected by filtration and
washed with cold 95% ethanol (3 × 50 mL). This salt was
suspended in 100 mL of distilled water, and 9.4 mL of aqueous
50% (w/w) sodium hydroxide was added, followed by 90 mL of
dichloromethane. After the mixture was stirred for 1 h, the
phases were separated and the aqueous phase was extracted
using dichloromethane (3 × 70 mL). The combined organic
phases were washed with 70 mL of saturated NaCl aqueous
solution, dried over sodium sulfate, and evaporated. This
treatment was repeated twice to obtain the d diamine 2b (5
g, ee ) 99% [HPLC]; yield of separation ) 85%) as a white
1
3
70%. H NMR (200 MHz, CDCl3): δ 1.29 (12H, t, J ) 7 Hz),
2.27 (6H, s), 2.50 (2H, bs), 3.66 (2H, s), 4.1 (8H, m), 7.15 (4H,
m), 7.45 (4H, m). 13C NMR (50 MHz, CDCl3): δ 16.2 (d, J C-P
3
2
1
) 6.4 Hz), 34.4, 62.0 (d, J C-P ) 5.3 Hz), 70.8, 127.0 (d, J C-P
) 188 Hz), 128.0 (d, J C-P ) 15 Hz), 131.4 (d, J C-P ) 10 Hz),
145.4. 31P NMR (81 MHz, CDCl3): δ 18.4.
20
deliquescent powder. [R]D 84.5 (c 1, CH2Cl2). The three
The above-mentioned oil (1.108 g, 2.16 mmol) was dissolved
in 15 mL of dichloromethane, and bromotrimethylsilane (2.9
mL, 21.6 mmol) was added in one portion and stirred at room
temperature under inert atmosphere for 2 days. The reaction
medium was evaporated under reduced pressure to obtain a
foamy solid to which methanol (15 mL) was added, and the
mixture was stirred for 1 day at ambient temperature.
combined mother liquors obtained above were concentrated
under vacuum, and the residue was stirred with 100 mL of
distilled water and 9.4 mL of aqueous 50% (w/w) sodium
hydroxide, followed by 90 mL of dichloromethane. After
stirring for 1 h, the phases were separated and the aqueous
phase was extracted using dichloromethane (3 × 70 mL). The
J . Org. Chem, Vol. 67, No. 23, 2002 8195

Maillet et al.
Methanol was then evaporated, and the residue was dissolved
in 10 mL of water. Upon addition of acetone, a white solid
appeared, which was filtered, washed with acetone, and dried
under vacuum to give 0.8 g of compound 2c as a white powder
(75% yield). 1H NMR (200 MHz, D2O): δ 2.60 (6H, s), 5.07
(2H, s), 7.20 (4H, m), 7.75 (4H, m). 31P NMR (81 MHz, D2O):
into 2.3 mL of distilled water, and 285 µL of 1 M sodium
hydroxide (5 equiv) was added. The resulting clear mixture
was thoroughly degassed, and 2.3 mL of a 0.1 M degassed
t-BuOK solution in isopropanol was added. Then, 7 mg [0.014
mmol] of [Rh(COD)Cl]2 were introduced, and the mixture was
stirred at 50 °C overnight. Finally, 67 µL of acetophenone [Rh/
substrate 5%] was injected into this yellow solution with a
syringe.
20
δ 11.9. l-2c: [R]D -62.7 (c 1, 1 M NaOH). Mp: 285 °C (dec.).
20
d-2c: [R]D 62.6 (c 1, 1 M NaOH). Mp: 285 °C (dec.). The
compounds were isolated in the form of their hydrobromide
monohydrate salt. Anal. Calcd for C16H22N2P2O6‚HBr‚H2O: P,
12.41; C, 38.49; H, 5.05; N, 5.61. Found: P, 12.48; C, 38.43;
H, 5.15; N, 5.57.
The reaction products obtained from the catalytic tests were
analyzed by gas chromatography (using the internal standard
method [nonane]) with a J & W Scientific DB-1701 column (l
) 30 m, i.d. ) 0.25 mm), equipped with a FID detector (N2 as
the carrier gas). The enantiomeric excesses of the various
alcohols (Table 2) formed were measured using a Machery-
Nagel LIPODEX E column (l ) 25 m, i.d. ) 0.25 mm, He as
the carrier gas); the configuration of the major enantiomer
formed was assigned by polarimetry, by comparison with
literature data.
Gen er a l Con d ition s for Hyd r ogen a tion u n d er Hyd r o-
gen P r essu r e. Ligand 2c (15 mg, 0.03 mmol) was suspended
into 3.75 mL of distilled water, and 150 µL of 1 M sodium
hydroxide (OH-/2c 5 equiv) was added. The resulting clear
mixture was thoroughly degassed using several vacuum/argon
cycles, and 3.75 mL of a degassed 4 × 10-3 M [Ir(COD)2]BF4
solution in methanol was added. Then, the mixture was stirred
at room temperature for 4 days under argon. The catalyst was
then transferred into a 30 mL stainless steel glass-coated
autoclave, and the substrate (with the desired iridium/
substrate molar ratio) was then introduced. The autoclave was
purged three times with argon, followed by three times with
hydrogen, and the final H2 pressure was adjusted to 45 atm
and heated at 50 °C. After 21 h of stirring, the autoclave was
allowed to cool and decompressed. The reaction mixture was
extracted several times using petroleum ether for analysis. The
compared reaction rates between the homogeneous (2b) and
biphasic (2c) systems were measured using an autoclave
(volume ) 300 mL) equipped with a sampling valve, a tubular
oven, an internal temperature probe, and a mechanical stirrer
(set at 1000 rpm). For each test, 75 mL of the catalyst solution
([Ir] ) 4 × 10-4 M) was used with a 0.1% iridium/substrate
ratio.
Ack n ow led gm en t. T.P. would like to thank the
French Ministry of Research for provision of a Postdoc-
toral Fellowship. The authors would like to thank M.
J . Bertrand for help in collecting GC data and M.
Lemaire (UMR CNRS 5622) for fruitful discussions.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 1, 2b, 3, and 2c (ester and acid form); X-ray
crystallographic data for compound d-3 and an ORTEP draw-
ing of the structure, corresponding to the (R,R)-enantiomer;
and experimental procedure for the separation of meso-2b and
d,l-2b on large-scale preparations. This material is available
free of charge via the Internet at http://pubs.acs.org.
Gen er a l Con d ition s for th e Hyd r id e Tr a n sfer Hyd r o-
gen a tion . Ligand 2c (28.5 mg, 0.057 mmol) was suspended
J O020506V
8196 J . Org. Chem., Vol. 67, No. 23, 2002