Synthesis of some new chiral cyclic o-hydroxylarylphosphonodiamides as ligands for asymmetric silylcyanation of aromatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2003.09.032

Some new chiral cyclic o-hydroxylarylphosphonodiamides were synthesized from (-)-α-phenylethylamine and found to be efficient ligands for the Ti(OPr-i)₄ catalyzed asymmetric trimethylsilylcyanation of aromatic aldehydes. Corresponding cyanohydr

Full text of DOI:10.1016/j.tetasy.2003.09.032

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3937–3941
Synthesis of some new chiral cyclic
o-hydroxylarylphosphonodiamides as ligands for asymmetric
silylcyanation of aromatic aldehydes
Zhuohong Yang, Zhenghong Zhou,* Ke He, Lixin Wang, Guofeng Zhao, Qilin Zhou and
Chuchi Tang*
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, PR China
Received 4 September 2003; accepted 12 September 2003
Abstract—Some new chiral cyclic o-hydroxylarylphosphonodiamides were synthesized from (−)-a-phenylethylamine and found to
be efficient ligands for the Ti(OPr-i )4 catalyzed asymmetric trimethylsilylcyanation of aromatic aldehydes. Corresponding
cyanohydrins were obtained in good chemical yield and enantiomeric excesses up to 90%.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
many effective chiral ligands have a free hydroxyl
group or an amino group bearing at least a N–H bond
which is favorable to form the Lewis acid center of the
catalyst by coordinating conveniently with the metal
atom in Lewis acid. Moreover, if a phosphoryl group
(PꢀO) is existed at an appropriate position in the ligand
molecule, the unshared electron pair on oxygen atom
should act as a Lewis base. In the catalyst, it contains
both a Lewis acid center and a Lewis base center,
namely, LALB catalyst. It is a new type of chiral
bifunctionalcatalyst.3dInthispaper,newcyclico-hydroxyl-
arylphosphonodiamides 3 were synthesized starting
from (−)-a-phenylethylamine and the catalytic effect of
the bifunctional catalyst formed in situ from 3 and
Ti(OPr-i )4 in asymmetric silylcyanation of aromatic
aldehydes were investigated.
Optically active cyanohydrins are important intermedi-
ates in organic synthesis for the synthesis of a variety of
valuable classes of chiral compounds, such as a-amino
acids, a-hydroxyl carboxylic acids, b-amino alcohols,
vicinal diols, a-hydroxyketones, etc. Many efficient
approaches have been reported for obtaining them by
biological and chemical methods.1 In the latter, the
most important one was the asymmetric silylcyanation
of aldehydes with trimethylsilylcyanide catalyzed by a
Lewis acid, such as Ti(OPr-i )4, TiCl4, AlCl3, R2AlCl,
SmCl3 etc. in the presence of a chiral ligand. In this
reaction, a wide range of chiral ligands have been
elaborated, such as Schiff bases,2 diols,3diamides,4
phosphorus compounds5 etc. As shown in literature,
* Corresponding authors. Fax: +86 22 23503438; e-mail: z.h.zhou@eyou.com; c.c.tang@eyou.com
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.032

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Z. Yang et al. / Tetrahedron: Asymmetry 14 (2003) 3937–3941
2. Results and discussion
The molar ratio of ligand 3 to Ti(OPr-i )4 was
observed to be an essential factor to the enantioselec-
tivity. It was found that the optimal molar ratio of
ligand 3 to Ti(OPr-i )4 is 4:1, which led to the corre-
sponding cyanohydrin in high chemical yield and rela-
tively good enantioselectivity (entries 2 and 1, 3, 4; 5
and 7, 8). Moreover, the amount of ligand had a
marked influence on the enantioselectivity of the reac-
tion. For example, the use of 40 mol% of ligand 3c
led to the desired cyanohydrin in high yield with ee
value of 90% (entry 5), while the use of 20 mol% and
10 mol% of 3c only gave moderate and low enan-
tioselectivity (entry 7, 62% ee; entry 8, 29% ee),
respectively. Additionally, the reaction temperature
also had an obvious influence on enantioselectivity.
For example, satisfactory result (entry 5, 90% ee) was
obtained when the reaction was carried out at 0°C,
whereas the enantioselectivity decreased when the
reaction was run at 20°C (entry 6, 73% ee). There-
fore, in most cases, the reaction was run at 0°C since
this reaction is extremely sluggish when carried out
below 0°C.
According to literature method,6 the reaction of (−)-a-
phenylethylamine and 1,2-dibromoethane in the pres-
ence of an acid binding agent readily led to
(−)-N,N%-di-a-phenylethyl ethylenediamine 1. Further
cyclization of 1 with O-aryl phosphorodichloridates
resulted in cyclic O-aryl phosphorodiamidates 2. The
stereoselective P–O to P–C rearrangement of 2 in the
presence of n-BuLi gave the title compounds cyclic
o-hydroxylarylphosphonodiamides 3. The similar rear-
rangement has also been reported by Buono et al.7
The catalytic effect of the chiral titanium complexes
prepared in situ from compound 3 and Ti(OPr-i )4 in
the asymmetric silylcyanation of aromatic aldehydes
were investigated. The results were listed in Table 1.
As shown in Table 1, in all cases, the corresponding
cyanohydrins was obtained in high chemical yields
varying from 80 to 98%. Furthermore, the (R)-
cyanohydrin was formed as the major enantiomer
whatever substrate was employed.5f,9
Table 1. Trimethylsilylcyanation of aromatic aldehydes catalyzed by 3/Ti(OPr-i )4
Entry
Ar
3 (mol%)
Ti(OPr-i )4 (mol%)
Temp. (°C)
Yield (%)a
[h]D (c 1, CHCl3)
Ee (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
3c (20)
3c (40)
3c (40)
3c (40)
3c (40)
3c (40)
3c (20)
3c (10)
3c (40)
3c (40)
3c (40)
3c (40)
3c (40)
3c (40)
3c (40)
3c (40)
3b (40)
3b (40)
3a (40)
3a (40)
10
10
20
40
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
0
0
0
0
0
20
0
0
0
0
90
98
90
98
92
86
86
86
92
80
95
96
90
96
96
90
90
98
90
98
+17.0
+19.1
+18.6
+14.0
+24.6
+19.8
+16.8
+8.0
+24.3
+30.6
+20.9
+6.1
+2.0
+9.2
+1.2
+11.2 (EtOH)
+9.5
38c
43c, 42.7b
41c
35c
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
4-MeOC6H4
2-MeC6H4
4-MeC6H4
4-ClC6H4
3-ClC6H4
2-NO2C6H4
3-NO2C6H4
2-Naphthyl
Ph
90d
73d
62d
29d
9
50e
10
11
12
13
14
15
16
17
18
19
20
72f
0
41g
10
10
10
10
0
0
0
0
0
15h
4i
8j
5k
76l
21c, 20.6b
43d
2-MeOC6H4
Ph
2-MeOC6H4
+11.8
+14.4
+11.3
32c, 31.7b
41d
a Isolated yield.
b Determined by GC with chiral column after derivation with acetic anhydride.
c Determined by the comparison of specific rotation values [h]D20 +45.0 (CHCl3).8
d [h]2D0 −21.0 (CHCl3) with 77% ee.1a
e [h]2D5 +49.0 (CHCl3).8
f [h]2D5 +21.3 (CHCl3) with 51% ee.9
g [h]2D5 +47.4 (CHCl3) with 92% ee.9
h [h]2D5 +27.2 (CHCl3) with 66% ee.9
i [h]2D5 +32.0 (CHCl3) with 57% ee.9
j [h]2D5 +56.0 (CHCl3) with 50% ee.9
k [h]2D5 +12.2 (CHCl3) with 29% ee.9
l [h]2D5 +10.9 (EtOH) with 73% ee.2c

Z. Yang et al. / Tetrahedron: Asymmetry 14 (2003) 3937–3941
3939
A series of aromatic aldehydes were used as substrate in
3c/Ti(OPr-i )4 catalyzed asymmetric silylcyanation
under the same condition. A significant variation in
enantiomeric excesses was observed depending on the
nature of the aldehydes. When there exists electron
withdrawing substituent (such as NO2, Cl) on benzene
ring, the enantioselectivity is quite low although the
chemical yield is excellent (entries 12–15); When elec-
tron donating group (such as MeO, Me) substituted
benzaldehydes and b-naphthyl aldehyde were employed
as substrate, moderate to satisfactory enantioselectivity
could be obtained. Furthermore, the enantioselectivity
was also influenced by the postion of the substituent on
benzene ring. The best result (90% ee) was obtained
with o-methoxybenzaldehyde (entry 5), while the enan-
tiomeric excesses of p-methoxybenzaldehyde was much
lower (entry 9, 50% ee). The same phenomena appeared
between o-methylbenzaldehyde and p-methylbenzalde-
hyde (entry 10, 11).
Me3SiCN was prepared according to the literature
procedure.10
4.1. Preparation of (−)-N,N%-di-a-phenylethyl ethylene-
diamine
To a mixture of 48.4 g (0.43 mol) of (−)-a-phenylethyl-
amine and 20.2 g (0.2 mol) of triethylamine was added
dropwise 18.8 g (0.1 mol) of 1,2-dibromoethane at
110°C under a nitrogen atmosphere. The resulting mix-
ture was stirred for another 22 h at 110–130°C. After
cooling to 60°C 150 mL of saturated KOH solution
was added carefully. The organic layer was separated
and the water layer was extracted with methylene chlo-
ride (3×100 mL). The combined organic phase was
washed successively with water, saturated brine and
dried over anhydrous sodium sulfate. After recovery of
excess (−)-a-phenylethylamine (25.0 g) the residue was
distilled under reduced pressure to afford 20.7 g
expected product, yield 77%, bp 162–163°C/133 Pa
[h]D=−65.9 (c 1, CHCl3) [Lit.6 [h]D=−69.2 (c 1,
CHCl3)].
It was also found the nature of the ligand 3 had an
obvious influence on enantioselectivity of the reaction.
The ee values of the ligand in which Ar% was an
(un)substituted hydroxyphenyl group (such as 3a and
3b) were less than those of ligand 3c in which Ar% was
a hydroxynaphthyl (entries 17, 19 and 2; 18, 20 and 5).
The introduction of a methyl group on the hydrox-
yphenyl group had no obvious influence on the
stereoselectivity (entries 17 and 19; 18 and 20). It seems
that the more bulky naphthyl group has a decisive
influence on the enantioselectivity of the reaction.
4.2. Preparation of O-aryl phosphorodiamidates 2 (gen-
eral procedure)
To a stirring mixture of (−)-N,N%-di-a-phenylethyl
ethylenediamine 1 (2.70 g, 10 mmol), Et3N (2.40 g, 24
mmol) and CH2Cl2 (40 mL) was added dropwise O-aryl
phosphorodichloridate (10 mmol) at 0°C. The resulting
mixture was stirred for 24 h at room temperature, then
adjusted to pH 7 with 2N aqueous NaOH. The organic
layer was separated and washed successively with dis-
tilled water and brine and dried over anhydrous magne-
sium sulfate. After removal of solvent the residue was
purified by column chromatography on silica gel (200–
300 mesh, 5:1 petroleum ether/ethyl acetate as eluent)
to afford the phosphorodiamidate 2.
3. Conclusion
In conclusion, a new type of chiral cyclic o-hydroxyl-
arylphosphonodiamides 3 has been synthesized starting
from (−)-a-phenylethylamine. The corresponding
cyanohydrins were obtained in high chemical yield in
titanium complex formed in situ from compound 3 and
Ti(OPr-i )4 catalyzed silylcyanation of aromatic alde-
hydes. The enantioselectivity of the reaction was deter-
mined by the nature of substrate and ligand employed,
the molar ratio of the ligand to Ti(OPr-i )4 as well as
the amount of the catalyst. The improvement of this
type of ligand for enhancing the ee value and decreas-
ing the amount of catalyst and the application of them
for other asymmetric reaction are continuing in our
laboratory.
4.2.1. (−)-O-Phenyl phosphorodiamidate 2a. Thick liq-
uid, yield: 86% [a]2D0=−3.5 (c 1, CHCl3). Anal. calcd.
for C24H27N2O2P: C, 70.92; H, 6.69; N, 6.89. Found: C,
1
70.85; H, 6.45; N, 6.70. H NMR (l, CDCl3): 1.54 (d,
3H, CH3), 1.71 (d, 3H, CH3), 2.86 (m, 4H, 2CH2), 4.40
(q, 2H, 2CH), 7.30 (m, 15H arom); 31P NMR (l,
CDCl3): 17.86.
4.2.2. (−)-O-4-Methylphenyl phosphorodiamidate 2b.
Thick liquid, yield: 76% [a]2D0=−3.0 (c1, CHCl3). Anal.
calcd. for C25H29N2O2P: C, 71.41; H, 6.95; N, 6.66.
Found: C, 71.11; H, 6.97; N, 6.79. 1H NMR (l,
CDCl3): 1.52 (d, 3H, CH3), 1.68 (d, 3H, CH3), 2.31 (s,
3H, CH3), 2.82 (m, 4H, 2CH2), 4.48 (m, 2H, 2CH), 7.23
(m, 14H arom); 31P NMR (l, CDCl3): 17.95.
4. Experimental
1H and 31P NMR were recorded in CDCl3 on a Bruker
AC-P200 instrument using TMS as an internal standard
1
for H NMR and 85% H3PO4 as an external standard
4.2.3. (+)-O-1-Naphthyl phosphorodiamidate 2c. Thick
liquid, yield: 84% [h]2D0=+11.8 (c 1, CHCl3). Anal.
calcd. for C29H29N2O2P: C, 73.67; H, 6.40; N, 6.14.
Found: C, 73.66; H, 6.44; N, 5.82. 1H NMR (l,
CDCl3): 1.26 (d, 3H, CH3), 1.68 (d, 3H, CH3), 2.95 (m,
4H, 2CH2), 4.50 (m, 2H, 2CH), 7.40 (m, 15H arom),
7.91 (m, 1H arom), 8.32 (m, 1H arom); 31P NMR (l,
CDCl3): 18.20.
for 31P NMR. Optical rotations were measured on a
Perkin-Elmer 241MC polarimeter. Elemental analyses
were conducted on a Yanaco CHN Corder MT-3 auto-
matic analyzer. Melting points were determined on a
T-3 melting point apparatus. All temperatures were
uncorrected. All of the solvent was used after dried and
redistillation. Ti(OPr-i )4 was purchased from Fluka.

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Z. Yang et al. / Tetrahedron: Asymmetry 14 (2003) 3937–3941
4.3. Preparation of o-hydroxylarylphosphonodiamides 3
After measuring the optical rotation, the cyanohydrin
was converted into the corresponding acetate by react-
ing with two equivalents of acetic anhydride in methyl-
ene chloride (20 mL) in the presence of pyridine at
room temperature for 12 h. The mixture was washed
sequentially with 5% H2SO4, distilled water and satu-
rated aqueous NaHCO3, and dried over anhydrous
sodium sulfate. After removal of solvent the crude
product was purified by column chromatography on
silica gel (200–300 mesh, 5:1 petroleum ether/ethyl ace-
tate as eluent) to give the acetylated cyanohydrin which
was analyzed by GC with chiral column for determin-
ing ee value.
(general procedure)
To a stirring solution of compound 2 (10 mmol) in
THF (60 mL) was added dropwise a solution of n-BuLi
(20 mmol, 1 M in hexane) at −78°C under a nitrogen
atmosphere. After 15 min the cold bath was removed
and the reaction mixture was poured into a mixture of
CH2Cl2 (150 mL) and saturated aqueous NH4Cl (30
mL). The organic layer was separated and dried over
anhydrous sodium sulfate. After removal of solvent the
crude product was purified by column chromatography
on silica gel (200–300 mesh, 5:1 petroleum ether/ethyl
acetate as eluent) to give compound 3.
Acknowledgements
4.3.1. (−)-2-Hydroxyphenylphosphonodiamide 3a. Thick
liquid, yield: 41% [h]2D0=−32.3 (c1, CHCl3). Anal.
calcd. for C24H27N2O2P: C, 70.92; H, 6.69; N, 6.89.
Found: C, 71.10; H, 6.64; N, 6.84. 1H NMR (l,
CDCl3): 1.40 (d, 3H, CH3), 1.51 (d, 3H, CH3), 2.98 (m,
4H, 2CH2), 4.31 (q, 2H, 2CH), 7.10 (m, 14H arom); 31P
NMR (l, CDCl3): 33.55.
We are grateful to the National Natural Science Foun-
dation of China (No. 20272025) and the PhD Programs
of Ministry of Education of China for generous finan-
cial support for our programs.
4.3.2. (−)-2-Hydroxy-5-methylphenylphosphonodiamide
3b. Thick liquid, yield: 36% [h]2D0=−13.6 (c1, CHCl3).
Anal. calcd. for C25H29N2O2P: C, 71.41; H, 6.95; N,
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4.4. The asymmetric silylcyanation of benzaldehyde
(typical procedure, entry 1)
To a solution of 3c (0.182 g, 0.4 mmol) in 5 mL of
methylene chloride was added Ti(OPr-i )4 (0.0286 g, 0.1
mmol) under a nitrogen atmosphere at room tempera-
ture and the resulting mixture was stirred for 1 h. Then
freshly distilled benzaldehyde (0.106 g, 1 mmol) and
trimethylsilyl cyanide (0.2 g, 2 mmol) were added to it
at 0°C and the whole stirred for 24 h at the same
temperature. The mixture was poured into a mixture of
1N hydrochloric acid (30 mL) and ethyl acetate (30
mL) and stirred vigorously for 4 h at room tempera-
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layer was extracted with ethyl acetate (2×20 mL). The
combined organic phase was washed with brine and
dried over anhydrous sodium sulfate. After removal of
solvent the crude product was purified by column chro-
matography on silica gel (200–300 mesh, 5:1 petroleum
ether/ethyl acetate as eluent) to afford 0.13 g of the
corresponding cyanohydrin.
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