C2-Symmetric diphenylphosphoramide and diphenylthiophosphoramide derived from (1R,2R)-1,2-diaminocyclohexane as ligands for the titanium(IV) alkoxide-promoted addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(99)00348-1

Chiral C₂-symmetric diphenylphosphoramide 4 and diphenylthiophosphoramide 5 were prepared from the reaction of diphenylphosphinic chloride and diphenylthiophosphinic chloride with (1R,2R)- (-)-1,2-diaminocyclohexane in the presence of diisoprop

Full text of DOI:10.1016/S0957-4166(99)00348-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3319–3325
C2-Symmetric diphenylphosphoramide and
diphenylthiophosphoramide derived from (1R,2R)-1,2-
diaminocyclohexane as ligands for the titanium(IV) alkoxide-
promoted addition of diethylzinc to aldehydes
Min Shi ∗ and Wen-Sheng Sui
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received 21 June 1999; accepted 21 July 1999
Abstract
Chiral C2-symmetric diphenylphosphoramide 4 and diphenylthiophosphoramide 5 were prepared from
the reaction of diphenylphosphinic chloride and diphenylthiophosphinic chloride with (1R,2R)-(−)-1,2-
diaminocyclohexane in the presence of diisopropylethylamine in high yields. They were used as chiral ligands in
the catalytic asymmetric addition reaction of diethylzinc to aldehydes in the presence of titanium(IV) isopropoxide
to give the corresponding sec-alcohols in 70–83% ee with an (R)-configuration and in 40–50% ee with an
(S)-configuration, respectively. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Catalytic asymmetric synthesis is a valuable method for preparing optically active substances.1
Concerning this subject, the stereoselective addition of organometallics to one of the two heterotopic
faces of a carbonyl group has been extensively studied: in particular, the addition of diethylzinc to
arylaldehydes has become a prototype in the evaluation of new chiral catalysts. So far, it is well known
that dialkylzinc is activated to react with aldehydes by the addition of a catalytic amount of chiral 1,2-,
1,3- and 1,4-diols, aminoalcohols and diamines.2 In addition, in the presence of titanium(IV) alkoxide
[Ti(OPri)4], chiral bidentate ligands such as the diol 1,3 ditriflamide 24 and tetradentate ligand 35 have
also been extensively and successfully used in the catalytic enantioselective addition of dialkylzinc to
aldehydes (Fig. 1). Ditriflamide 2 especially is an excellent chiral ligand for this asymmetric addition
reaction and its mechanistic detail has recently been disclosed by Walsh et al. through the crystal structure
∗
Corresponding author.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00348-1

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Figure 1.
of bis(sulfonamido) titanium bis(alkoxide) complexes.6 They found that sulfonyl oxygens are actually
bonded to the titanium center with Ti–O distances ranging from 2.249(3) to 2.390(3) Å combined with
the Ti–N bond. The coordination of the titanium–sulfonyl oxygens maintains a rigid C2-symmetric
environment and is an important factor in the transfer of the chirality. This result stimulated us to
study the chiral C2-symmetric phosphoramide and C2-symmetric thiophosphoramide for this asymmetric
addition reaction simply because it is conceivable that phosphoryl oxygen atoms and sulfur atoms could
coordinate to the titanium metal center as well and these novel chiral ligands could promote a high chiral
induction. Based on this concept, we started to prepare the chiral C2-symmetric phosphoramide 4 and
chiral C2-symmetric thiophosphoramide 5 and used them as catalytic chiral ligands for titanium(IV)
alkoxide-promoted asymmetric addition reaction of diethylzinc to aldehydes.
2. Results and discussion
Diphenylphosphoramide 4 and diphenylthiophosphoramide 5 were synthesized from the
reaction of diphenylphosphinic chloride and diphenylthiophosphinic chloride with (1R,2R)-(−)-
1,2-diaminocyclohexane in the presence of diisopropylethylamine in dichloromethane, respectively
(Scheme 1). After usual workup and purification by silica gel column chromatography, compounds 4
and 5 were obtained as colorless solids in over 90% yields. Those C2-symmetric chiral ligands were
used in the addition reaction of diethylzinc to p-chlorophenylaldehyde in the presence of titanium(IV)
isopropoxide [RCHO:Ti(OPri)4:Et2Zn=1:1.4:1.8]. In fact, the addition product, sec-alcohol, was
obtained in 92% yield and 22% ee (enantiomeric excess) in the presence of 4 mol% of 4 (0.04 equiv.)
in toluene (Table 1, entry 1). The ees of the product were determined by HPLC analysis using chiral
stationary-phase columns (Chiralcel OD and OJ) and the absolute configuration of the major enantiomer
was assigned according to the sign of the specific rotation. The ee of sec-alcohol could be improved by
increasing the amount of chiral ligand 4. The better result was obtained by using 20 mol% of 4 in toluene
with 40% ee (Table 1, entry 4). From Table 1, it is very clear that the chiral C2-symmetric phosphoramide
4 must have a so-called ‘ligand acceleration effect’,7 i.e. the reactivity of the active species bearing the
chiral ligand was enhanced. That is why the ee of the product could be increased with the increase of
the amount of chiral ligand. In the meantime, we found that the solvent drastically affected the ee of
this asymmetric addition reaction. Toluene and dichloromethane are good solvents for achieving higher
ees (40 and 50%) and the lowest ee of sec-alcohol was obtained in tetrahydrofuran (THF), although the
yields of the reaction products are very similar. The addition of molecular sieve 4A did not improve

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the enantioselectivity (Table 1, entry 3). Moreover, although it is convenient if this asymmetric addition
reaction is carried out at 0°C because the reaction is very sluggish at very low temperature (−50°C), we
found that the reaction temperature drastically affects the ee of the reaction product. For example, the
ee decreased to 22% at 7°C, but could reach 66% at −5°C and 81% at −20°C (Table 1, entries 7, 8, 9).
The best result was obtained in Table 1, entry 9. By means of this optimized reaction condition, various
aldehydes were used as substrates for this addition reaction and the corresponding sec-alcohol could be
obtained in 80–99% yield and 70–83% ee with R-configuration. The results are summarized in Table 2.
It should be emphasized that the chiral C2-symmetric ligand phosphoramide 4 could be recovered from
the reaction mixture in 90% after usual workup and can be used again in the asymmetric reaction without
loss of enantioselectivity. Thus, the chiral C2-symmetric phosphoramide is a quite effective chiral ligand.
We suggest that the phosphoryl oxygen atoms can coordinate to the titanium center as well as maintain
a rigid chiral C2-symmetric environment and thus achieve a high enantioselectivity. In order to verify
this coordination, we tried to isolate the active complex from the reaction of 4 with the mixed amide
alkoxide complex Ti(NMe)2(OPri)2,6 but despite extensive efforts, we did not obtain a single crystal
which could be subjected to X-ray crystal analysis.
Scheme 1.
On the other hand, it is well known that the sulfur-containing compounds such as substituted β-
aminothiols8 and β-hydroxysulfides derived from D-camphor9 are very effective chiral ligands for the
Table 1
Asymmetric addition reaction of diethylzinc to p-chlorobenzaldehyde in the presence of chiral ligand
4 under different reaction conditions

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Table 2
Asymmetric addition reaction of diethylzinc to arylaldehydes in the presence of a catalytic amount of
chiral ligand 4 [4:RCHO:Ti(OPri)4:Et2Zn=0.2:1:1.4:1.8]
enantioselective addition reaction of aldehydes and reduction of imides. Thus, we prepared chiral C2-
symmetric diphenylthiophosphoramide 5 and used it as chiral ligand in the same asymmetric addition
reaction. The reaction was carried out in the same manner as when using chiral ligand 4. Surprisingly,
we found that the sec-alcohol was obtained preferentially with the S-configuration, i.e. inversion of
enantioselectivity was observed compared to when using the chiral ligand 4, although the ee was not
as high (31% at −5°C and 40% at −20°C) (Table 3). The best result was obtained in toluene at −20°C.
The chiral ligand 5 can also be recovered from the reaction mixture in 60% after usual workup and can be
used again without loss of enantioselectivity. At present the mechanistic detail of this interesting inversion
phenomenon remains obscure and work to elucidate this is in progress. As one explanation, we think that
the different electron withdrawing ability of the P_S and P_O bonds may play an important role in
this interesting inversion of enantioselectivity. The higher electron withdrawing ability of the P_O bond
(atomic electronegativity: O: 3.52, S: 2.52, P: 2.11) causes the higher acidity of NH proton in 4. Thus it
can readily exchange the ligand with Ti(OPri)4 to give the complex A, just like ditriflamide 2 (Fig. 2).6
However, for diphenylthiophosphoramide 5, due to the lower acidity of NH proton in 5, no ligand
exchange could take place and complex B may be the active chiral Lewis acid for its enantioselective
addition reaction (Fig. 2). Namely, the structural difference of the active species might cause the inversion
of the enantioselectivity between chiral ligands 4 and 5.
By means of the optimized reaction conditions, various aldehydes were used as substrates for the same
addition reaction using 5 as a catalytic ligand and the corresponding sec-alcohol could be obtained in
80–99% yield and 40–50% ee with the S-configuration. The results are summarized in Table 4.
In conclusion, the chiral bidentate C2-symmetric phosphoramide 4 and thiophosphoramide 5 were
found to be a new class of effective chiral ligands for the titanium-promoted enantioselective addition

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Table 3
Asymmetric addition reaction of diethylzinc to p-chlorobenzaldehyde in the presence of chiral ligand
5 under different reaction conditions
Figure 2.
Table 4
Asymmetric addition reaction of diethylzinc to arylaldehydes in the presence of a catalytic amount of
chiral ligand 5 [5:RCHO:Ti(OPri)4:Et2Zn=0.2:1:1.4:1.8] in dichloromethane

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reaction of dialkylzinc reagents to aldehydes although they are not as effective as ditriflamide 2.4 These
results should lead to the design and synthesis of new chiral ligands. Efforts are underway to elucidate
the mechanistic details of this addition reaction and to disclose the exact structure of the active species.
Moreover, we are planning to synthesize other similar bidentate C2-symmetric chiral phosphoramides in
order to seek out more effective and stereoselective chiral ligands and to utilize these novel chiral ligands
to the other catalytic asymmetric reactions.
3. Experimental
3.1. General
Mps were obtained with a Yanagimoto micro melting point apparatus and are uncorrected. Optical
rotations were determined in a solution of CHCl3 at 20°C by using a Perkin–Elmer 241 MC polarimeter;
[α]D values are given in units of 10−1 deg cm2 g−1. 1H NMR spectra were recorded on a Bruker AM-300
spectrometer for solution in CDCl3 with tetramethylsilane (TMS) as internal standard; J values are in
hertz. Mass spectra were recorded with an HP-5989 instrument and HRMS was measured by a Finnigan
MA+ mass spectrometer. Organic solvents used were dried by standard methods when necessary. All
solid compounds reported in this paper gave satisfactory CHN microanalyses with an Italian Carlo–Erba
1106 analyzer. Commercially obtained reagents were used without further purification. All reactions
were monitored by TLC with Huanghai 60F254 silica gel coated plates. Flash column chromatography
was carried out using 300–400 mesh silica gel at increased pressure. All ethylation experiments were
performed under argon using standard Schlenk techniques. The optical purities of sec-alcohols were
determined by HPLC analysis using a chiral stationary phase column (column, Daicel Co. Chiralcel OD
and OJ; eluent, 100:0.5–2 hexane–2-propanol mixture; flow rate, 1.0 ml min−1; detection, 254 nm light)
and absolute configuration of the major enantiomer was assigned according to the sign of the specific
rotation.
3.2. Preparation of chiral phosphoramide 4
To a solution of (1R,2R)-(−)-1,2-diaminocyclohexane (182 mg, 1.60 mmol) and diisopropylethylamine
(724 mg, 5.60 mmol) in dichloromethane was added diphenylphosphinic chloride (757 mg, 3.20 mmol)
at −30°C. After stirring of the mixture for 6 h, the reaction mixture was washed with 3% aq. HCl, water,
10% Na2CO3 and brine and the product was extracted with ether. The extract was dried over MgSO4, and
then evaporated under reduced pressure. The residue was purified by silica gel column chromatography
to give the compound 4 (740 mg, 90%). Mp 196–198°C; [α]D +40.5 (c 1, CHCl3); δH (CDCl3) 1.0–1.20
(2H, m, CH2), 1.22–1.49 (2H, m, CH2), 1.50–1.72 (2H, m, CH2), 1.80–2.10 (2H, m), 2.90–3.10 (2H, m),
4.40–4.60 (2H, m), 7.30–7.40 (4H, m, Ar), 7.40–7.60 (8H, m, Ar), 7.70–7.90 (4H, m, Ar), 7.95–8.12 (4H,
m, Ar); MS (EI) m/z (%): 514 (M+, 5.4), 313 (50), 297 (40), 270 (45), 201 (100). Found: C, 70.17; H,
6.30; N, 5.40%. HRMS (EI) m/z: 514.1961 (M+); C30H32N2O2P2 requires: C, 70.03; H, 6.27; N, 5.44%;
M, 514.1939.
3.3. Preparation of chiral thiophosphoramide 5
This compound was prepared in the same manner as that described above. To a solution of (1R,2R)-
(−)-1,2-diaminocyclohexane (158 mg, 1.38 mmol) and diisopropylethylamine (536 mg, 4.15 mmol) in

M. Shi, W.-S. Sui / Tetrahedron: Asymmetry 10 (1999) 3319–3325
3325
dichloromethane was added diphenylthiophosphinic chloride (702 mg, 2.78 mmol) to give 5 as a colorless
solid (693 mg, 92%). Mp 84–85°C; [α]D +18.9 (c 1.3, CHCl3); δH (CDCl3) 0.80–1.72 (6H, m, CH2),
1.80–2.00 (2H, m), 3.20–3.45 (2H, m), 3.90–4.20 (2H, m), 7.20–7.60 (12H, m, Ar), 7.70–7.90 (4H, m,
Ar), 7.95–8.12 (4H, m, Ar); MS (EI) m/z (%): 547 (MH+, 5.4), 513 (5.4), 328 (59.7), 313 (90.3), 217
(100). Found: C, 65.87; H, 5.81; N, 5.20%. HRMS (EI) m/z: 546.1499 (M+). C30H32N2S2P2 requires: C,
65.91; H, 5.90; N, 5.12%; 546.1482.
3.4. Typical reaction procedure
To a solution of phosphoramide 4 (103 mg, 0.2 mmol) in dichloromethane was added titanium(IV)
isopropoxide (398 mg, 1.4 mmol) at room temperature. After stirring of the mixture for 0.5 h, p-
chlorobenzaldehyde (140 mg, 1.0 mmol) was added into the reaction solution and the reaction mixture
was cooled to −50°C. Then diethylzinc (1.80 ml, 1.80 mmol, 1 M solution in hexane) was added into the
solution and the reaction mixture was stirred for 48 h at −20°C. The reaction was quenched by 5% aq.
HCl and the product was extracted with ether. The organic layer was washed with brine and dried over
MgSO4, and then evaporated under reduced pressure. The residue was purified by silica gel TLC to give
the optically active 1-(p-chlorophenyl)propan-1-ol (162 mg, 95%).
Acknowledgements
We thank Prof. Albert S. C. Chan and the National Natural Sciences Foundation of China for financial
support.
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