Enantioselective addition of diethylzinc to N-diphenylphosphinoylimines employing N,N-dialkyl-1,2-diphenyl-2-aminoethanols as chiral ligands

Article abstract of DOI:10.1016/S0040-4039(01)01273-4

By fine-tuning the substituents on the nitrogen of (1S,2R) and (1R,2S)-1,2-diphenyl-2-aminoethanols, a chiral ligand 2b was obtained, which showed excellent enantioselectivity, with up to 94% e.e, for the asymmetric addition of diethylzinc to N-diphenylphosphinoylimines 1. In one example, the optically active amide 3c was converted into a new amine 5 with 98% e.e. by a reaction sequence involving Suzuki coupling and hydrolysis without racemization.

Full text of DOI:10.1016/S0040-4039(01)01273-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6369–6372
Enantioselective addition of diethylzinc to
N-diphenylphosphinoylimines employing
N,N-dialkyl-1,2-diphenyl-2-aminoethanols as chiral ligands
Xiaomei Zhang,a Liuzhu Gong,a,* Aiqiao Mi,a,* Xin Cui,a Yaozhong Jiang,a Michael C. K. Choib
and Albert S. C. Chanb
aUnion Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu,
610041, China
bOpen Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong, China
Received 20 April 2001; accepted 12 July 2001
Abstract—By fine-tuning the substituents on the nitrogen of (1S,2R) and (1R,2S)-1,2-diphenyl-2-aminoethanols, a chiral ligand 2b
was obtained, which showed excellent enantioselectivity, with up to 94% e.e, for the asymmetric addition of diethylzinc to
N-diphenylphosphinoylimines 1. In one example, the optically active amide 3c was converted into a new amine 5 with 98% e.e.
by a reaction sequence involving Suzuki coupling and hydrolysis without racemization. © 2001 Elsevier Science Ltd. All rights
reserved.
As is widely known, optically active amines play impor-
tant roles in the synthesis of natural products and
physiologically active substances.1 Moreover, optically
active amines are employed extensively as resolving
reagents2 and as chiral auxiliaries in asymmetric synthe-
sis.3 Enantioselective addition of dialkylzinc reagents to
imines is a convenient route to optically active amines.
There have been several reports of enantioselective
addition of dialkylzincs to imines employing chiral
aminoalcohols,4 polymeric chiral aminoalcohols5 and
H
Chiral ligand 2
Ph
N
Ph
Ph
Ph
N
Ph
Ph
*
+ Et2Zn
P
P
Toluene, r.t.
O
Et
O
1a
3a
Chiral ligands:
Ph
HO
Ph
Ph
HO
Ph
Ph
Ph
N
Ph
Ph
Bn
C6H11
N(n-C4H9)2
N
HO
HO
NMe2
Me
Me
(1R,2S)-2d
(1R,2S)-2b
(1S,2R)-2a
(1R,2S)-2c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
iPr
Bn
HO
N
HO
N
HO
N
HO
Me
Me
(1R,2S)-2e
(1S,2S)-2h
(1R,2S)-2f
(1R,2S)-2g
Scheme 1. Asymmetric diethylzinc addition to N-diphenylphosphinoylimine 1a promoted by 2a–h.
Keywords: diethylzinc addition; imines; aminoalcohols; Suzuki coupling.
* Corresponding authors. E-mail: ulas@china.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01273-4

6370
X. Zhang et al. / Tetrahedron Letters 42 (2001) 6369–6372
ally restricted aminoalcohols,4d,f the use of nitrogen
constrained ligands 2f and 2g as promoters resulted in
a dramatic drop in both yields and enantioselectivities
(entries 7 and 8), perhaps due to the rigidity of the
pyrrolidine ring in the ligands that made it difficult for
ligand–zinc alkoxides to coordinate with the substrates.
A comparison of entries 2 and 9 shows that the configu-
ration of the product depends on the configuration of
the carbon bonded to the hydroxyl group in the lig-
ands. When the configuration of this carbon is inverted,
but that of the carbon bonded to nitrogen remained, as
shown by 2b and 2h, the configuration of the product is
inverted from R to S. The erythro ligand 2b showed
much better enantioselectivity than the threo ligand 2h.
Lowering the catalyst loading from stoichiometric to 50
mol% led to a decrease in yield, even if the reaction was
prolonged to 72 h, but the e.e. remained high (entry 3).
chiral dendrimers6 as ligands. Generally, conformation-
ally restricted aminoalcohols exhibit higher enantiose-
lectivity.4d,f Recently, Tomioka and co-workers
reported their work on the copper–amidophosphine
catalyzed asymmetric addition of organozincs to imines
with excellent results.7
The complexes of chiral 1,2-diphenyl-2-aminoethanol
and its derivatives have been investigated for promoting
several reactions in our laboratory, and have exhibited
high enantioselectivities in most cases.8 Prompted by
these results and the fact that the size of the substituent
on chiral aminoalcohols bonded to the nitrogen might
play an important role in the enantioselectivity,4c,d we
have proposed that highly enantioselective ligands for
asymmetric diethylzinc addition to N-diphenylphosphi-
noylimines 1 might be obtained by fine-tuning of the
substituents on the nitrogen of the chiral 1,2-diphenyl-
2-aminoethanol.
The optimal ligand (1R,2S)-2b was utilized for the
asymmetric addition of diethylzinc to various imines
(Scheme 2). As shown in Table 2, most of the reactions
proceeded smoothly to provide the corresponding chiral
diphenylphosphinoyl amides 3 in good yields with
enantiomeric excesses higher than 90%. The poor yield
and low e.e. of the adduct from the imine 1h may be
due to the steric hindrance imposed by the di-ortho-
substituted benzene ring (entry 8). A variety of optically
active amines may be easily obtained by acidic hydroly-
sis of the diphenylphosphinoyl amides 3.11
Chiral ligands 2a–h were prepared from 1,2-diphenyl-2-
aminoethanol according to the literature.9 The results
of imine 1a reacting with Et2Zn in the presence of a
stoichiometric amount of 2a–h in toluene at room
temperature10 (Scheme 1) are presented in Table 1.
It was found that the size of the substituents bonded to
the nitrogen on ligands 2 was very important for
achieving high enantioselectivity in the reactions. The
ligand (1S,2R)-2a, which is excellent for enantioselec-
tive diethylzinc addition to aldehydes,8a also directed
addition to 1a with 91% e.e. (entry 1). A slight improve-
ment on the enantioselectivity was realized when the
reaction was catalyzed by 2b. Further increase in the
steric hindrance of the substituents on nitrogen of the
chiral ligands led to a significant decrease in enantiose-
lectivity (entries 4–8). Unlike the known conformation-
Through a simple Suzuki coupling,15 3c was converted
to 416 without racemization. After hydrolysis of 4, the
optically active amine 5 was obtained with 98% e.e.
(Scheme 3). This sequence of reactions provides a
promising method to synthesize a wide range of opti-
cally active amines.
Table 1. Asymmetric diethylzinc addition to N-diphenylphosphinoylimine 1a promoted by the ligands 2a–ha
Entry
Ligand (equiv.)
Time (h)
Yield (%)b
E.e. (%)c
Config.d
1
2
3
4
5
6
7
8
9
(1S,2R)-2a (1.0)
(1R,2S)-2b (1.0)
(1R,2S)-2b (0.5)
(1R,2S)-2c (1.0)
(1R,2S)-2d (1.0)
(1R,2S)-2e (1.0)
(1R,2S)-2f (1.0)
(1R,2S)-2g (1.0)
(1S,2S)-2h (1.0)
48
48
72
48
48
48
48
48
48
76
90
67
72
75
91
65
69
92
91
94
90
89
88
85
80
78
40
S
R
R
R
R
R
R
R
S
a Molar ratio 1a:Et2Zn:2=1:4:0.5–1
b Isolated yield.
c Determined by HPLC analysis on a chiral column (Chiralcel OD).
d Determined by comparison of the retention time with the literature.4
H
H3O+
A
r
NH
2
Chiral ligand 2b
Ar
N
Ph
Ph
A
r
NPh
Ph
*
*
+ Et2Zn
P
P
then OH-
Toluene, r.t., 48 h
Et
Et
O
O
1a-h
3a-h
Scheme 2. Asymmetric diethylzinc addition to N-diphenylphosphinoylimines 1a–h promoted by 2b.

X. Zhang et al. / Tetrahedron Letters 42 (2001) 6369–6372
6371
Table 2. Asymmetric diethylzinc addition to N-diphenylphosphinoylimine 1a–h promoted by the ligand 2b
Entry
Ar
Imine
Adduct
Yield (%)
E.e. (%)a
1
2
3
4
5
C6H5-
1a
1b
1c
1d
1e
3a
3b
3c
90
84
90
59
86
94
92
p-ClC6H4-
p-BrC6H4-
p-CH3OC6H4-
91(96)b
93
3d
3e12
93
6
7
8
p-CH3C6H4-
m-CH3C6H4-
2,4,6-tri CH3C6H2-
1f
1g
1h
3f
79
90
22
94
92
76
3g13
3h14
a Determined by HPLC analysis on a chiral column (Chiralcel OD or Chiralcel AD).
b E.e was obtained after recrystallization.
Br
Ph
Pd(PPh3)4
H
H
Ph
Ph
Ph
Ph
+ PhB(OH)2
N
N
*
*
P
P
2M K2CO3(aq.),THF
Reflux
Et
O
Et
O
3c (96% e.e.)
4 (86%, 96% e.e., 98% e.e.
after recrystallization)
Ph
H3O+
then OH-
NH2
*
Et
5 (99%, 98% e.ea)
a Determined by HPLC analysis using a chiral column (Chiralcel AD) after derivation of the amine to
the corresponding acetamide.
Scheme 3. Preparation of chiral amine 5 from 3c by a reaction sequence of Suzuki coupling and hydrolysis.
In summary, we have demonstrated the use of a series
of N,N-dialkyl-1,2-diphenyl-2-aminoethanols for the
asymmetric addition of diethylzinc to N-diphenylphos-
phinoylimines. The chiral ligand 2b which is effective in
asymmetric induction was obtained by fine-tuning of
the substituents bonded to the nitrogen on the chiral
aminoalcohols. The configuration of the product
depended upon the configuration of the carbon bonded
to the hydroxyl group in the ligand. Further conversion
of N-(1-p-bromophenylpropyl)-P,P-diphenylphosphi-
noylamide to optically active 1-p-phenylphenylpropyl-
amine, without racemization, by a reaction sequence
involving a Suzuki coupling and hydrolysis provided a
potentially facile method to synthesize a wide range of
chiral amines.
References
1. Moser, H.; Rihs, G.; Sauter, H. Z. Naturforsch. 1982, 37,
451.
2. Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Race-
mates and Resolution; John Wiley and Sons: New York,
1981.
3. Whitesell, J. K. Chem. Rev. 1989, 89, 1581.
4. (a) Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem. Soc.,
Chem. Commun. 1992, 1097; (b) Andersson, P. G.; Gui-
jarro, D.; Tanner, D. Synlett 1996, 727; (c) Andersson, P.
G.; Guijarro, D.; Tanner, D. J. Org. Chem. 1997, 62, 7364;
(d) Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem.
1998, 63, 2530; (e) Brandt, P.; Hedberg, C.; Lawonn, K.;
Pinho, P.; Andersson, P. G. Chem. Eur. J. 1999, 5, 1692;
(f) Jimeno, C.; Reddy, K. S.; Sola, L.; Moyano, A.; Pericas,
M. A.; Riera, A. Org. Lett. 2000, 2, 3157.
Acknowledgements
5. Soai, K.; Suzuki, T.; Shono, T. J. Chem. Soc., Chem.
Commun. 1994, 317.
6. Suzuki, T.; Hirokawa, Y.; Ohtake, K.; Shibata, T.; Soai,
K. Tetrahedron: Asymmetry 1997, 8, 4033.
7. Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc.
We are grateful for the financial support from the
National Science Foundation of China (29790124) and
The Hong Kong Polytechnic University ASD Fund.
2000, 122, 12055.

6372
X. Zhang et al. / Tetrahedron Letters 42 (2001) 6369–6372
8. (a) Li, S. J.; Jiang, Y. Z.; Mi, A. Q. Tetrahedron: Asym-
(Ar), 131.7 (Ar), 131.8 (Ar), 132.3 (Ar), 132.4 (Ar), 132.5
(Ar), 134.0 (Ar), 137.5 (Ar), 146.4 (Ar), 147.6 (Ar).
metry 1992, 3, 1467; (b) Mi, A. Q.; Wang, Z. Y.; Jiang,
Y. Z. Tetrahedron: Asymmetry 1993, 4, 1957; (c) Mi, A.
Q.; Wang, Z. Y.; Chen, Z. W.; Jiang, Y. Z.; Chan, A. S.
C.; Yang, T. K. Tetrahedron: Asymmetry 1995, 6, 2641;
(d) Jiang, Y. Z.; Zhou, X. G.; Hu, W. H; Wu, L. J.; Mi,
A. Q. Tetrahedron: Asymmetry 1995, 6, 405; (e) Jiang, Y.
Z.; Qin, Y.; Mi, A. Q.; Huang, Z. T. Tetrahedron:
Asymmetry 1994, 5, 1211; (f) Mi, A. Q.; Lou, R. L.;
Jiang, Y. Z.; Deng, J. G.; Qin, Y.; Fu, F. M.; Li, Z.; Hu,
W. H; Chan, A. S. C. Synlett 1998, 847.
13. N-[1-(3-Methylphenyl)propyl]-P,P-diphenylphosphinoyl-
1
amide 3g: H NMR (300 MHz, CDCl3): l (ppm) 0.78 (t,
3H, J=7.3 Hz, CH3CH2), 1.79–1.91 (m, 1H, CH2CH3),
1.95–2.06 (m, 1H, CH2CH3), 2.32 (s, 3H, CH3Ar), 3.30–
3.33 (m, 1H, NH), 4.02–4.09 (m, 1H, CHNH), 6.92–7.07
(m, 3H, Ar-H), 7.20–7.27 (m, 1H, Ar-H), 7.35–7.48 (m,
6H, Ar-H), 7.77–7.88 (m, 4H, Ar-H); 13C NMR (75
MHz, CDCl3): l (ppm) 10.5 (CH3), 21.4 (CH3Ar), 32.3
(CH2), 57.1 (CHNH), 123.4 (Ar), 127.3 (Ar), 127.7 (Ar),
128.1 (Ar), 128.2 (Ar), 128.3 (Ar), 128.4 (Ar), 131.6 (Ar),
131.7 (Ar), 131.8 (Ar), 132.5 (Ar), 132.6 (Ar), 137.9 (Ar),
143.2 (Ar), 143.3 (Ar).
9. Jiang, Y. Z.; Mi, A. Q.; Wang, Z. Y.; Li, S. J. YOUJI
HUAXUE 1994, 14, 68.
10. Typical experimental procedure for the enantioselective
addition of diethylzinc to N-diphenylphosphinoyl imine
1a in the presence of 2b: Imine 1a (30.5 mg, 0.1 mmol)
and ligand 2b (31.7 mg, 0.1 mmol) were dissolved in
toluene (1.5 mL) under argon. To the mixture was added
Et2Zn in hexane (1 M, 0.5 mL, 0.5 mmol) at rt. After
stirring for 48 h, the reaction was quenched with satu-
rated aqueous ammonium chloride, the aqueous layer
was extracted with CH2Cl2. The combined organic layer
was washed with brine, and dried over anhydrous
Na2SO4. After evaporation of the solvent, the residue was
purified by column chromatography on silica gel to give
3a (30.3 mg, 0.090 mmol, 90%) as a white solid. The
enantiomeric excess of 94% with R-enantiomer predomi-
nating was determined by HPLC (Chiracel OD column,
hexane/propan-2-ol=95:5); flow rate 1 mL/min; R-iso-
mer, tR 12.58 min and S-isomer, tR 18.15 min)
11. Ramage, R.; Hopton, D.; Parrott, M. J.; Kenner, G. W.;
Moore, G. A. J. Chem. Soc., Perkin Trans. 1 1984, 1357.
12. N-(1-Piperonylpropyl)-P,P-diphenylphosphinoylamide 3e:
1H NMR (300 MHz, CDCl3): l (ppm) 0.78 (t, 3H, J=7.4
Hz, CH3CH2), 1.73–1.85 (m, 1H, CH2CH3), 1.91–2.05
(m, 1H, CH2CH3), 3.25 (m, 1H, NH), 4.02–4.04 (m, 1H,
CHNH), 5.94–5.95 (m, 2H, OCH2O), 6.55–6.59 (m, 1H,
Ar-H), 6.69–6.71 (m, 2H, Ar-H), 7.35–7.48 (m, 6H, Ar-
H), 7.75–7.95 (m, 4H, Ar-H); 13C NMR (75 MHz,
CDCl3): l (ppm) 10.5 (CH3), 32.4 (CH2), 56.9 (CHNH),
100.9 (OCH2O), 106.7 (Ar), 107.9 (Ar), 119.9 (Ar), 128.1
(Ar), 128.2 (Ar), 128.3 (Ar), 128.4 (Ar), 131.5 (Ar), 131.6
14. N-[1-(2,4,6-Trimethylphenyl)propyl]-P,P-diphenylphosphi-
1
noylamide 3h: H NMR (300 MHz, CDCl3): l (ppm) 0.89
(t, 3H, J=7.8 Hz, CH3CH2), 1.70 (s, 3H, CH3Ar), 1.88–
1.98 (m, 1H, CH2CH3), 2.00–2.12 (m, 1H, CH2CH3), 2.25
(s, 3H, CH3Ar), 2.52 (s, 3H, CH3Ar), 3.37 (m, 1H, NH),
4.49–4.59 (m, 1H, CHNH), 6.65 (s, 1H, Ar-H), 6.84 (s,
1H, Ar-H), 7.26–7.28 (m, 2H, Ar-H), 7.42–7.46 (m, 4H,
Ar-H), 7.67–7.71 (m, 2H, Ar-H), 7.90–7.93 (m, 2H, Ar-
H); 13C NMR (75 MHz, CDCl3): l (ppm) 11.3 (CH3),
20.4 (CH3Ar), 20.6 (CH3Ar), 20.8 (CH3Ar), 30.1 (CH2),
52.8 (CHNH), 128.0 (Ar), 128.1 (Ar), 128.3 (Ar), 128.5
(Ar), 129.0 (Ar), 130.9 (Ar), 131.1 (Ar), 131.5 (Ar), 131.7
(Ar), 132.6 (Ar), 132.7 (Ar), 135.9 (Ar), 136.1 (Ar), 136.2
(Ar).
15. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun.
1981, 11, 513; (b) Suzuki, A. Acc. Chem. Res. 1982, 15,
178.
1
16. N-(1-Biphenylpropyl)-P,P-diphenylphosphinoylamide 4: H
NMR (300 MHz, CDCl3): l (ppm) 0.84 (t, 3H, J=7.3
Hz, CH3CH2), 1.84–1.94 (m, 1H, CH2CH3), 1.96–2.10
(m, 1H, CH2CH3), 3.43–3.44 (m, 1H, NH), 4.14–4.16 (m,
1H, CHNH), 7.23–7.62 (m, 15H, Ar-H), 7.76–7.94 (m,
4H, Ar-H); 13C NMR (75 MHz, CDCl3): l (ppm) 10.6
(CH3), 32.8 (CH2), 57.2 (CHNH), 126.9 (Ar), 127.1 (Ar),
127.2 (Ar), 128.1 (Ar), 128.5 (Ar), 128.7 (Ar), 131.7 (Ar),
131.9 (Ar), 139.8 (Ar), 140.7 (Ar), 143.8 (Ar), 143.9 (Ar);
98% ee, [h]2D0=+80.4 (c=1.0, CHCl3).
.