Evaluation of chiral oxazolines for the highly enantioselective diethylzinc addition to N-(diphenylphosphinoyl) imines

Article abstract of DOI:10.1021/jo0268862

On the basis of the principle that the incorporation of the structurally rigid and conformationally restricted skeleton in β-amino alcohols is beneficial to the enantioselective diethylzinc addition to imines, a series of chiral oxazolines, which had been

Full text of DOI:10.1021/jo0268862

Eva lu a tion of Ch ir a l Oxa zolin es for th e High ly En a n tioselective
Dieth ylzin c Ad d ition to N-(Dip h en ylp h osp h in oyl) Im in es†
Xiao-Mei Zhang,‡ Hai-Le Zhang,‡ Wen-Qing Lin, Liu-Zhu Gong,* Ai-Qiao Mi,* Xin Cui,
Yao-Zhong J iang, and Kai-Bei Yu
Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu, 610041, China
gonglz@cioc.ac.cn
Received December 19, 2002
On the basis of the principle that the incorporation of the structurally rigid and conformationally
restricted skeleton in â-amino alcohols is beneficial to the enantioselective diethylzinc addition to
imines, a series of chiral oxazolines, which had been designed and conveniently prepared from
commercially available (1S,2S)-2-amino-1-phenylpropane-1,3-diol, were applied in the diethylzinc
addition to diphenylphosphinoyl imines to give high yields of 68-84% and excellent ee values of
90-95%. The configuration of the product was controlled by the chirality of the carbon bonded to
the hydroxyl group in the oxazoline. Oxazolines bearing a para- or meta-substituted phenyl group
generally offered higher enantioselectivity than those containing an ortho-substituted phenyl. The
X-ray structures of 4f and 4j, in combination with the proposed transition state, preliminarily
explained why oxazolines with a para- or meta-substituent on the phenyl group gave higher
enantioselectivities than those bearing an ortho-substituent. This successful example using chiral
oxazolines to promote the titled reaction implies that a large family of chiral compounds containing
an oxazoline ring moiety have the potential to be developed for promoting the highly enantioselective
dialkylzinc addition to N-(diphenylphosphinoyl) imines.
In tr od u ction
reduction of prochiral imines and enamides,4 the asym-
metric addition of nucleophiles to imines is one of the
most convenient methodologies for this purpose.5 Highly
enantioselective addition of diethylzinc to imines leading
to optically active amines has been attracting increasing
attention since the pioneer work reported by Soai in 1992,
whose group used the ephedrine derivative (1) as a chiral
ligand in the diethylzinc addition to N-(diphenylphos-
phinoyl) imines, leading to excellent enantioselectivity.6a
Many chiral ligands have been designed for promoting
this transformation, but most of them are limited to the
derivatives of chiral amino alcohols.6a-g,7 In particular,
the conformationally restricted and structurally rigid
artificial amino alcohols (2, 3) generally exhibit higher
The design of economical and efficient chiral ligands
for highly enantioselective transformations has been one
of the major projects in asymmetric synthesis.1 Carbon-
carbon bond-forming reactions are among the most useful
methodologies for the construction of complex natural
and unnatural molecules. Optically active amines are
very important intermediates for the synthesis of some
natural products, physiologically active substances, and
pharmaceutical compounds.2 Nevertheless, they are also
extensively applied to the resolution of racemic com-
pounds and asymmetric synthesis as chiral auxiliaries.3
For all of these reasons, the development of efficient
methods for approaching chiral amines has been receiv-
ing much attention. Other than the enantioselective
(4) (a) Burk, M. J .; Wang, Y. M.; Lee, J . R. J . Am. Chem. Soc. 1996,
118, 5142. (b) Burk, M. J .; Casy, G.; J ohnson, N. B. J . Org. Chem.
1998, 63, 6084. (c) Zhang, F. Y.; Pai, C. C.; Chan, A. S. C. J . Am. Chem.
Soc. 1998, 120, 5808. (d) Zhu, G. X.; Zhang, X. M. J . Org. Chem. 1998,
63, 9590. (e) Yan, Y. Y.; RajanBabu, T. V. Org. Lett. 2000, 2, 4137.
(5) (a) Denmark, S. E.; Nicaise, O. J .-C. J . Chem. Soc., Chem.
Commun. 1996, 999. (b) Denmark, S. E.; Nicaise, O. J .-C. In Compre-
hensive Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer-Verlag: Berlin, 1999; p 923. (c) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069.
(6) (a) Soai, K.; Hatanaka, T.; Miyazawa, T. J . Chem. Soc., Chem.
Commun. 1992, 1097. (b) Andersson, P. G.; Guijarro, 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) J imeno,
C.; Reddy, K. S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera, A. Org.
Lett. 2000, 2, 3157. (g) Sato, I.; Kodaka, R.; Soai, K. J . Chem. Soc.,
Perkin Trans. 1 2001, 2912. (h) Zhang, X. M.; Lin, W. Q.; Gong, L. Z.;
Mi, A. Q.; Cui, X.; J iang, Y. Z.; Choi, M. C. K.; Chan, A. S. C.
Tetrahedron Lett. 2002, 43, 1535-1537.
† This paper is dedicated to professor Zhi-Tang Huang at the
Institute of Chemistry, Chinese Academy of Sciences, on the occasion
of his 75th birthday.
‡ X.-M. Zhang and H.-L. Zhang contributed equally to this work.
* Corresponding author.
(1) (a) Comprehensive Asymmetric Catalysis; J acobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds; Springer-Verlag: Berlin, 1999. (b) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994.
(c) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York,
1993. (d) Principle and Application of Asymmetric Synthesis; Lin, G.-
Q., Li, Y.-M., Chan, A. S. C.; Wiley-Interscience, J ohn Wiley and
Sons: 2001.
(2) (a) Moser, H.; Rihs, G.; Sauter, H. Z. Naturforsch. B. 1982, 37
(4), 451. (b) Bloch, R. Chem. Rev. 1998, 98, 1407. (c) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry, 1997, 8, 1895. (d) J ohansson,
A. Contemp. Org. Synth. 1995, 2, 393.
(3) (a) J acques, J .; Collet, A.; Wilen, S. H. In Enantiomers, Race-
mates, and Resolution; J ohn Wiley and Sons: New York, 1981. (b)
Whitesell, J . K. Chem. Rev. 1989, 89, 1581.
10.1021/jo0268862 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/25/2003
4322
J . Org. Chem. 2003, 68, 4322-4329

Evaluation of Chiral Oxazolines
SCHEME 1 a
enantioselectivities than those induced by their simple
and flexible analogues, but they suffer from the incon-
venience associated with their multistep syntheses.6e-f
Our continuous efforts have been devoted to evaluating
easily accessible chiral ligands for highly enantioselective
diethylzinc addition to imines, for example, fine-tuning
the size of the substituents bonded to nitrogen has shown
that a N-monosubstituted 1,2-diphenyl-2-aminoethanol
efficiently promotes diethylzinc addition to imine with
the high enantioselectivity of 98% ee.7a To find more
efficient and easily prepared ligands for this addition,
families of chiral ligands with a diversity of structures
other than amino alcohols still need to be designed.
a
Reagents and conditions: (a) RCOCl (1 equiv) or (PhCO)2O
(for synthesis of 6a , 1 equiv), Et3N, THF, rt. (b) TsCl (1 equiv),
Et3N, CH2Cl2, reflux, 51-80%. (c) R1CH2COCl (2 equiv), NaHCO3,
H2O, rt. (d) K2CO3, CH3OH, rt, 54% (6d ) and 71% (6e) (two steps).
Resu lts a n d Discu ssion
We envisioned that chiral oxazolines with a backbone
similar to 1 had three structural characteristics that
might enable them to be the promising candidates in
competition with amino alcohols in promoting the dieth-
ylzinc addition of N-(diphenylphosphinoyl) imines. (1)
They have sp2-hybridized nitrogens, the conformations
of which, restricted by the oxazoline ring, might make
the structure of the ligand rigid, thereby minimizing the
diastereomers formed in the transition state during
catalysis. Such a transition state might be conductive to
the chiral information of the carbon adjacent to hydroxyl
group efficiently transmitting to the product. (2) The
oxygen in the oxazoline ring is conjugated with CdN,
which causes the nitrogen to be more Lewis basic, thus
changing the Lewis acidity and catalytic activity of their
zinc complexes. (3) The chiral environment could be
systematically modified for the high enantioselectivity by
fine-tuning the size of R groups in 4. Our preliminary
results on the use of chiral oxazolines in promoting
diethylzinc addition to imines with high enantioselectiv-
ity have been presented previously.6h Herein, we would
like to present our more extensive study on application
of chiral oxazolines in the titled reaction.
P r ep a r a tion of Oxa zolin es. The synthesis of the
family of chiral oxazolines is very convenient, beginning
with an amidition of (1S,2S)-2-amino-1-phenyl-propane-
1,3-diol with RCOCl or (RCO)2O to provide amides 6a -k
according to the literature in high yields.8 Among these
compounds, 6b, 6h , 6i, and 6k were sufficiently pure for
the next step without further purification (Scheme 1).
Mixtures of over-acylation products 7a and 7b and the
desired products 6d and 6e were observed when we
followed a procedure similar to the synthesis of 6d and
6e. Partial hydrolysis of the mixture of 7a , 7b, 6d , and
6e in the presence of K2CO3 in methanol furnished the
single products 6d and 6e. Compounds 6a -k were
treated with TsCl and Et3N to provide the corresponding
chiral oxazolines 4a -k in good to high yields (Table 1).
High-quality crystals of 4f and 4j suitable for X-ray
structural determination were obtained by slow evapora-
tion from a mixture of CH2Cl2 and petroleum ether (see
Supporting Information). It was found that the difference
between oxazolines 4f and 4j existed in dihedral angles
of the oxazoline ring and its conjugated substituted
phenyl group. In oxazoline 4f, the dihedral angle formed
between oxazoline and o-bromophenyl is 42.45°, much
larger than that formed between oxazoline and p-meth-
ylphenyl in oxazoline 4j (18.62°). This means that an
ortho-substitued phenyl group twists more out of conju-
gation with the oxazoline ring than a para- or meta-
substituted phenyl group does, bringing subtle changes
to the conformation of the transition state to influence
the enantioselectivities and reaction rate. In line with
the structural analysis for the oxazolines, we anticipate
that oxazolines with an ortho-substitued phenyl group
will have more influence on the enantioselectivity than
those bearing a para- or meta-phenyl group.
(7) (a) Zhang, H.-L.; Zhang, X.-M.; Gong, L.-Z.; Mi, A.-Q.; Cui, X.;
J iang, Y.-Z.; Choi, M. C. K.; Chan, A. S. C. Org. Lett. 2002, 4, 1399.
(b) Zhang, X.; Gong, L.; Mi, A.; Cui, X.; J iang, Y.; Choi, M. C. K.; Chan,
A. S. C. Tetrahedron Lett. 2001, 42, 6369-6372.
(8) (a) Rozwadowska, M. D. Tetrahedron: Asymmetry 1998, 9, 1615.
(b) Poelert, M. A.; Hulshof, L. A.; Kellogg, R. M. Recl. Trav. Chim.
Pay-Bas, 1994, 113, 355.
F IGURE 1. Chiral oxazolines used for present study.
J . Org. Chem, Vol. 68, No. 11, 2003 4323

Zhang et al.
TABLE 1. Syn th esis of Oxa zolin es 4a -k
TABLE 2. En a n tioselective Dieth ylzin c Ad d ition of
N-Dip h en ylp h osp h in oyl Ben za lim in e (9a ) in th e
amides 6
R
yield (%)a
oxazoline 4
yield (%)
P r esen ce of th e Ch ir a l Oxa zolin es 4 a n d 5a
6a
6b
6c
6d
6e
6f
6g
6h
6i
Ph
iPr
Naph
94
b
4a
4b
4c
4d
4e
4f
4g
4h
4i
80
80
63
51
51
60
65
50
53
61
56
91
54
71
86
99
b
b
96
b
Bn
CH2Naph
2-BrC6H4
4-BrC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
entry
ligands
yield (%)b
ee (%)c
configurationd
1
2
3
4
5
6
7
8
9
10
11
12
13
4a
4b
4c
4d
4e
4f
4g
4h
4i
77
62
79
70
65
35
86
77
72
89
91
56
55
91
85
85
87
84
81
92
84
93
91
92
76
23
S
S
S
S
S
S
S
S
S
S
S
R
S
6j
6k
4j
4k
a
b
Isolated yields for amides 6. Products were directly used in
the next step without further purification.
SCHEME 2a
4j
4k
4l
5
a
Reaction was carried out at room temperature in the presence
b
of a stoichiometric amount of oxazoline for 48 h. Isolated yield
based on imine. c Determined on HPLC. Determined by com-
d
parison of the retention time with literature values.6
hydroxyl group. When the configuration of this carbon
was inverted, but that of the carbon bonded to the
nitrogen in oxazoline ring maintained, as shown by 4a
and 4l, the configuration of the product 10a was inverted
from S to R (entries 1 and 12); however, the enantiose-
lectivity had a small decrease to 76% ee. Varying the size
of the R group bonded to oxazoline ring resulted in a
subtle change in the enantioselectivity (entries 1-5). It
seemed that the enantioselectivity did not rely on the
steric hindrance of the R group. Among 4a -e, chiral
oxazoline ligand 4a , in which R was a phenyl group,
showed the highest level of chiral induction for the
diethylzinc addition to imine 9a , giving an ee of 91%. On
the basis of the X-ray structures of 4f and 4j (see
Supporting Information), we expected that the R′ sub-
stituents bonded to the phenyl group at different posi-
tions might exhibit an obvious effect on the enantiose-
lectivity. As we expected, the substituent at different
positions on the phenyl in oxazoline exhibited a dramatic
influence on the reaction (entries 6-11). In general,
oxazolines bearing an ortho-substituted phenyl group
would provide lower enantioselectivity than their ana-
logues containing a phenyl group with para or meta-
substituents. This might result from ortho-substituents
causing the phenyl group to twist out of conjugation with
the CdN double bond of oxazoline to form a distorted
transition state upon coodination with diethylzinc, which
is more unstable than that formed by oxazolines bearing
para- or meta-substituted phenyl groups. The observation
is also in agreement with our analysis. For example,
oxazoline 4g, having a p-bromophenyl group, promoted
the diethylzinc addition to N-diphenylphosphinoyl ben-
zalimine (9a ), leading to a much higher enantioselectivity
of 92% ee (entry 7) than that of 81% ee (entry 6) given
by its analogue 4f, which poccessed an o-bromophenyl
group. Similar results were also observed with oxazolines
4h -j. Compound 4i, bearing a m-methylphenyl group,
and 4j, bearing a p-methylphenyl group, provided excel-
lent enantioselectivities of 93 and 91% ee, respectively
a
Reagents and conditions: (a) Ph3P, DEAD, THF, reflux, 21%.
(b) K2CO3, CH3OH, rt, 84%.
To clarify the influence of chirality of the carbon
bonded to the hydroxy group, the oxazoline 4l was
prepared from 4a by a Mitsunobu configuration inversion
reaction sequence (Scheme 2).9 The treatment of 4a with
PPh3 and DEAD in refluxing THF gave 8 in 21% yield,
which was directly subjected to a hydrolysis in the
presence of K2CO3 to furnish 4l in 84% yield (Scheme 2).
Liga n d Su r vey. The different chiral oxazolines 4 and
5 were examined for the addition of diethylzinc to
N-diphenylphosphinoyl benzalimine (9a ) leading to N-(1-
phenylpropyl)-diphenylphosphinoyl amide 10a to find the
optimal ligand. The nonpolar solvent toluene, which was
found to maximize the rate difference between the
catalyzed and the noncatalyzed reaction, was used as the
reaction medium.6b-e The results of imine 9a reacting
with Et2Zn in the presence of a stoichiometric amount of
4 and 5 in toluene at room temperature are summarized
in Table 2.
It was found that this set of chiral oxazoline ligands
were efficient and highly enantioselective for the titled
reaction. High ee values of 81-93% were induced by most
of the oxazolines 4a -k (entries 1-11). The chiral carbon
bonded to the hydroxyl group in the ligand was very
important for getting high enantioselectivity. Without
this chiral center, oxazoline 5 gave a very low ee value
of 23% (entry 13). The configuration of the product was
also controlled by the chiral carbon bonded to the
(9) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org. Prep.
Proc. 1996, 28, 127.
4324 J . Org. Chem., Vol. 68, No. 11, 2003

Evaluation of Chiral Oxazolines
TABLE 3. Asym m etr ic Dieth ylzin c Ad d ition to N-Dip h en ylp h osp h in oylim in es 9a -g P r om oted by th e Liga n d 4a a n d 4k
a
b
Isolated yield. Determined by HPLC analysis on a chiral column (Chiralcel OD or Chiralcel AD).
(entries 9 and 10), higher than that of 84% offered by 4h
containing an o-methylphenyl group (entry 8).
En a n tioselective Dieth ylzin c Ad d ition to Im in es.
Ligands 4a and 4k were extended to promote the
diethylzinc addition to a range of diphenylphosphi-
noylimines. The corresponding results are recorded in
Table 3. In the presence of ligand 4a , ee values from 90
to 93% were obtained for all of the imine substrates
tested. The substituents on the substrates did not exhibit
any obvious effect on the enantioselectivity. Ligand 4k ,
on average, gave slightly higher ee values of up to 95%,
higher than the ee values of ligand 4a for all of the
substrates examined except for imine 9f. Imine 9f reacted
with diethylzinc to provide chiral amide in 92% ee
mediated by 4k , a small amount lower than the ee value
of 93% provided by 4a .
By comparison of well-known ligands such as 1-3 for
this transformation, we found that oxazoline 4k exhibited
higher enantioselectivity than 1 (up to 91% ee)6a and
similar enantioselectivity as 2 (up to 95% ee),6f only a
small amount lower than ligand 3 developed by Ander-
sson and co-workers (98% ee).6e However, our ligand 4k
is much easier to prepare.
Rea ction Mech a n ism . Andersson and co-workers
proposed a transition state to explain the diethylzinc
addition to imine on the basis of calculation.6e A structur-
ally restricted chiral â-amino alcohol was evaluated on
the basis of the transition state for diethylzinc addition
to imine with high enantioselectivity. Our design of the
oxazoline ligands was also based on the conclusion that
conformationally restricted and structurally rigid artifi-
cial amino alcohols generally exhibited higher enanti-
oselectivities than those induced by their simple and
flexible analogues; therefore, we believed that the mech-
anism in our case should be similar to that proposed by
Andersson and co-workers, as shown in Figure 2.6e This
transition state accounted for the results we observed.
As shown in structure I, products with S absolute
configuration should be given by 4a -k , which was
consistent with the experimental results (Table 2, entries
1-11). The transition state, as demonstrated in II, clearly
F IGURE 2. Proposed transition state for the titled reaction.
explained that the oxazoline containing an ortho-sub-
stituent on phenyl offered much greater effects on the
enantioselectivity than that with a para- or meta-sub-
stituent. X-ray structures of 4f and 4j indicated that the
repulsion brought about by the ortho-substituent on
phenyl of oxazoline coordinated with zinc made the
phenyl group twist out of conjugation with the oxazoline
ring, which might form a much more unstable, that is,
high-energy, transition state with a twisted conformation
in comparison with the zinc complex of oxazoline with a
para- or meta-substituted phenyl. Therefore, oxazolines
with a para- or meta-substituent gave higher enantiose-
lectivities than their structural analogues bearing an
ortho-substituted phenyl group.
Con clu sion
In conclusion, a series of chiral oxazolines were con-
veniently synthesized from commercial materials. Their
application in activating diethylzinc addition to aromatic
N-diphenylphosphinoylimines led to high yields and
excellent ee values of 91-95%. The configuration of the
product was controlled by the chirality of the carbon
bonded to the hydroxyl group in the oxazoline. The X-ray
structures of 4f and 4j combining with the proposed
transition state explained that the oxazolines with a
para- or meta-subsituent on the phenyl group gave higher
J . Org. Chem, Vol. 68, No. 11, 2003 4325

Zhang et al.
(PhCO+). Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16.
Found: C, 70.63; H, 6.45; N, 5.08.
enantioselectivities than those bearing an ortho-substitu-
ent. This successful example using chiral oxazolines to
promote the tilted reaction implied that a large family
of chiral compounds containing an oxazoline ring moiety
had the potential to be developed for promoting the
highly enantioselective dialkylzinc addition to N-diphe-
nylphosphinoylimines.
P r ep a r a tion a n d Ch a r a cter iza tion of (1S,2S)-2-(1′-
Na p h th oyla m in o)-1-p h en yl-p r op a n e-1,3-d iol (6c). To a
solution of (1S,2S)-2-amino-1-phenyl-propane-1,3-diol (0.334
g, 2.0 mmol) in anhydrous THF (20 mL) were added Et3N (3
mL) and 1-naphthoyl chloride (0.381 g, 2.0 mmol). After the
reaction mixture was stirred at room temperature for 16 h,
the solvent was evaporated under reduced pressure. To the
residue was added water (20 mL), and the resulting mixture
was extracted with chloroform (3 × 20 mL). The combined
organic layer was washed with 1 N HCl (20 mL) and dried
over anhydrous Na2SO4. After removal of the solvent, the
residue was recrystallized from a solvent mixture of PE,
benzene, and ethyl acetate to give 6c (0.587 g, 1.82 mmol, 91%)
as white crystals: mp 144-145 °C; [R]D +16.4 (c 1.0, EtOH);
IR (Nujol; cm-1) 3428, 3277, 1635; 1H NMR (300 MHz, CDCl3)
δ (ppm) 2.38-2.40 (br, 2H), 4.01-4.03 (m, 2H), 4.41-4.50 (m,
1H), 5.21 (d, J ) 3.6 Hz, 1H), 6.57 (d, J ) 1.4 Hz, 1H), 7.37-
7.48 (m, 9H), 7.88-7.91 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 56.8, 64.0, 73.8, 124.6, 124.9, 125.2, 125.7, 126.3, 127.0,
127.8, 128.1, 129.7, 130.6, 133.4, 133.9, 141.0, 170.4; MS (CI)
m/e 322 (M + H+), 303 (M - H2O), 285 (M - 2H2O), 272 (M -
H2O - CH2OH), 214 (M - PhCHOH), 197 (M - PhCHOH -
OH), 155 (NaphCO+). Anal. Calcd for C20H19NO3: C, 74.75;
H, 5.96; N, 4.36. Found: C, 74.37; H, 6.12; N, 4.34.
Exp er im en ta l Section
Gen er a l. All air- and moisture-sensitive reactions were
carried out under a dry argon atmosphere using standard
Schlenk line techniques. Toluene and THF were dried with
sodium/benzophenone. CH2Cl2 was dried with CaH2. Petro-
leum ether (PE) and ethyl acetate for column chromatography
were distilled before use.
Ma ter ia ls. Commercial starting materials were used di-
rectly. The N-diphenylphosphinoylimines 9a ,10-12,14 9b,12-14
6a,16
9c,11,12,15 9d ,13,14 and 9f
were prepared according to the
literature.10-16 Ligand 5 was also prepared according to the
literature.8a
N -P ip e r on ylm e t h ylid e n e -P ,P -d ip h e n ylp h osp h in a -
m id e (9e). This compound was prepared following a literature
procedure14 in 44% yield as a pale yellow solid: mp 154-155
°C; IR (Nujol; cm-1) 1616, 1270, 1200; 1H NMR (300 MHz,
CDCl3) δ (ppm) 6.08-6.09 (m, 2H), 6.90-6.96 (m, 1H), 7.35-
7.63 (m, 8H), 7.90-7.97 (m, 4H), 9.18 (d, J H-P ) 33.0 Hz, 1
H); 13C NMR (75 MHz, CDCl3) δ (ppm) 101.9, 106.8, 107.2,
108.3, 128.3, 128.4, 128.5, 128.6, 128.8, 130.7, 131.0, 131.4,
131.5, 131.6, 131.8, 132.3, 133.9, 148.5, 152.5, 171.8; MS (CI)
m/e 349 (M+), 272 (M - Ph), 202 (Ph2POH+), 201 (Ph2PO+).
Anal. Calcd for C20H16NO3P: C, 68.77; H, 4.62; N, 4.01.
Found: C, 69.09; H, 4.74; N, 4.14.
N-(3-Met h ylp h en ylm et h ylid en e)-P ,P -d ip h en ylp h os-
p h in a m id e (9g). This compound was prepared following a
literature procedure14 in 54% yield as a pale yellow solid: mp
116-118 °C; IR (Nujol; cm-1) 1628, 1200; 1H NMR (300 MHz,
CDCl3) δ (ppm) 2.45 (s, 3H), 7.40-7.51 (m, 8H), 7.69-7.97 (m,
6H), 9.30 (d, J H-P ) 33.0 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
δ (ppm) 21.2, 127.8, 128.3, 128.5, 128.7, 130.2, 131.4, 131.6,
131.7, 131.8, 132.1, 133.7, 134.5, 138.7, 173.8, 173.9; MS (CI)
m/e 319 (M+), 242 (M - Ph), 216 (Ph2PONH+), 202 (Ph2POH+),
201 (Ph2PO+). Anal. Calcd for C20H18NOP: C, 75.22; H, 5.68;
N, 4.39. Found: C, 75.29; H, 5.53; N, 4.48.
P r ep a r a tion a n d Ch a r a cter iza tion of (1S,2S)-2-Ben -
zoyla m in o-1-p h en yl-p r op a n e-1,3-d iol (6a ). To a solution
of (1S,2S)-2-amino-1-phenyl-propane-1,3-diol (0.501 g, 3.0
mmol) in anhydrous THF (20 mL) were added Et3N (5 mL)
and benzoyl anhydride (0.678 g, 3.0 mmol). After the reaction
mixture was stirred at room temperature for 16 h, the solvent
was evaporated under the reduced pressure. The resulting
residue was washed with water three times to give 6a (0.765
g, 2.82 mmol, 94%) as a white solid: mp 192-195 °C; [R]D
+94.6 (c 1.0, EtOH); IR (Nujol; cm-1) 3400, 3330, 3190, 1630;
1H NMR (300 MHz, DMSO-d6) δ (ppm) 3.37-3.42 (m, 1H),
4.17-4.19 (m, 1H), 4.75-4.79 (m, 1H), 4.93-4.96 (m, 1H), 5.51
(d, J ) 5.4 Hz, 1H), 7.19-7.50 (m, 8H), 7.75-7.77 (m, 3H);
13C NMR (75 MHz, DMSO-d6) δ (ppm) 57.5, 60.8, 70.7, 126.5,
127.1, 127.6, 128.1, 128.5, 131.4, 135.0, 143.9, 166.6; MS (CI)
m/e 272 (M + H+), 240 (M - CH2OH), 222 (M - CH2OH -
H2O), 164 (M - PhCHOH), 147 (M - PhCHOH - OH), 105
P r ep a r a tion a n d Ch a r a cter iza tion of (1S,2S)-2-P h e-
n yla cetyla m in o-1-p h en yl-p r op a n e-1,3-d iol (6d ). To a solu-
tion of (1S,2S)-2-amino-1-phenyl-propane-1,3-diol (1.67 g, 10.0
mmol) and NaHCO3 (6.8 g, 80.0 mmol) in water (80 mL) was
added phenylacetyl chloride (5 mL, 35 mmol) via an addition
funnel for 0.5 h at room temperature. After being stirred for
8 h, the mixture was extracted with dichloromethane (3 × 50
mL). The combined organic layer was washed with brine and
dried over Na2SO4. After removal of the solvent, to the
resulting residue were added K2CO3 (3.0 g, 22 mmol) and
methanol (300 mL). The mixture was stirred at room temper-
ature for 12 h, and then the methanol was evaporated. To the
residue was added water (100 mL), and the mixture was
extracted with dichloromethane (3 × 50 mL). The combined
organic layer was washed with brine and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure, the
residue was purified through column chromatography on silica
gel to provide 6d (1.537 g, 5.4 mmol, 54%) as white crystals:
mp 97-100 °C; [R]D +64.3 (c 1.0, CHCl3); IR (Nujol; cm-1) 3420,
1
3385, 3329, 3231, 1658; H NMR (300 MHz, CDCl3) δ (ppm)
3.48 (d, J ) 1.8 Hz, 2H), 3.75-3.78 (m, 2H), 4.02-4.04 (m,
1H), 4.99 (d, J ) 3.4 Hz, 1H), 6.19 (d, J ) 7.7 Hz, 1H), 7.10-
7.18 (m, 2H), 7.27-7.34 (m, 8H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 43.3, 56.6, 62.8, 72.5, 125.6, 127.2, 127.5, 128.2, 128.8,
129.2, 134.3, 141.0, 172.3; MS(CI) 267 (M - H2O), 236 (M -
H2O - CH2OH), 178 (M - PhCHOH), 161 (PhCH2CONHCH-
CH2+), 107 (PhCHOH+), 91 (PhCH2+). Anal. Calcd for C17H19
-
NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.27; H, 6.80; N,
5.11.
P r ep a r a tion of (1S,2S)-2-(1-Na p h th yla cetyla m in o)-1-
p h en yl-p r op a n e-1,3-d iol (6e). To a solution of (1S,2S)-2-
amino-1-phenyl-propanediol (0.334 g, 2 mmol) and NaHCO3
(1.0 g, 12.0 mmol) in water (20 mL) was added a solution of
1-naphthylacetyl chloride (0.818 g, 4 mmol) in dichloromethane
(5 mL) via an addition funnel at room temperature. After being
stirred for 50 h, the mixture was extracted with dichlo-
romethane (3 × 20 mL). The combined organic layer was
washed with brine and dried over anhydrous Na2SO4. After
removal of the solvent, to the resulting residue were added
K2CO3 (1.0 g, 7.1 mmol) and methanol (50 mL). The mixture
was stirred at room temperature for 18 h, then the methanol
was evaporated. To the residue was added water (20 mL), and
the mixture was extracted with dichloromethane (3 × 20 mL).
The combined organic layer was washed with 1 N HCl and
brine and dried over anhydrous Na2SO4. The solvent was
removed to provide 6e (0.474 g, 1.42 mmol, 71%) as a white
(10) Krzyzanowska, B.; Stec, W. J . Synthesis 1978, 521.
(11) Boyd, D. R.; J ennings, W. B.; McGuckin, R. M.; Rutherford, M.;
Saket, B. M. J . Chem. Soc., Chem. Commun. 1985, 582.
(12) Boyd, D. R.; Malone, J . F.; McGuckin, R. M.; J ennings, W. B.;
Rutherford, M.; Saket, B. M. J . Chem. Soc., Perkin Trans. 2 1988, 1145.
(13) J ennings, W. B.; Lovely, C. J . Tetrahedron Lett. 1988, 29, 3725.
(14) J ennings, W. B.; Lovely, C. J . Tetrahedron 1991, 47, 5561.
(15) Cantrill, A. A.; Hall, L. D.; J arvis, A. N.; Osborn, H. M. I.;
Raphy, J .; Sweeney, J . B. J . Chem. Soc., Chem. Commun. 1996, 2631.
(16) Hou, X. L.; Yang, X. F.; Dai. L. X.; Chen, X. F. Chem. Commun.
1998, 747.
4326 J . Org. Chem., Vol. 68, No. 11, 2003

Evaluation of Chiral Oxazolines
solid. The crude product was used in the following reaction
without purification.
CDCl3) δ (ppm) 69.4, 73.0, 76.5, 127.0, 127.2, 128.2, 128.3,
128.4, 128.5, 131.6, 140.0, 165.3; MS(CI) 254 (M + H+), 236
(M - OH), 147 (M + H - PhCHOH), 105 (PhCO+). Anal. Calcd
for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 76.00;
H, 5.93; N, 5.43.
Other analogues of 4a , except 4b, were prepared in a
manner similar to that described above and on the same
reaction scale (6 mmol scale).
P r ep a r a tion of (1S,2S)-2-(2′-Br om oben zoyla m in o)-1-
p h en yl-p r op a n e-1,3-d iol (6f). To a solution of (1S,2S)-2-
amino-1-phenyl-propanediol (836 mg, 5 mmol) in dichlo-
romethane (30 mL) and anhydrous triethylamine (10 mL) was
added 2-bromobenzoyl chloride (1097 mg, 5 mmol). After the
reaction mixture was stirred at room temperature for 8 h,
evaporation of the solvent under reduced pressure provided a
white solid. Washing the solid with water and drying gave 6f
(1.51 g) in 86% yield: mp 135-136 °C; IR (Nujol; cm-1) 3400,
3330, 3190, 1630; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 3.36-
3.41 (m, 1H), 3.59-3.67 (m, 1H), 4.09-4.15 (m, 1H), 4.82-
4.86 (m, 1H), 4.94-4.97 (m, 1H), 5.41 (d, J ) 5.7 Hz, 1H),
7.15-7.40 (m, 8H), 7.58 (d, J ) 7.8 Hz, 1H), 7.89 (d, J ) 8.7
Hz, 1H); 13C NMR (300 MHz, DMSO-d6) δ (ppm) 57.2, 60.6,
70.2, 119.2, 126.6, 127.1, 127.7, 128.1, 129.1, 131.1, 133.0,
139.4, 143.7, 167.3; MS (CI) m/e 77, 91, 118, 146, 155, 157,
183 (79BrPhCO+, 100%), 185 (81BrPhCO+, 100%), 225, 227, 242
(M - PhCHOH - 1), 244. Anal. Calcd for C16H16BrNO3: C,
54.87; H, 4.60; N, 4.00. Found: C, 54.51; H, 4.64; N, 3.79.
[(S,S)-2-(1′-Na p h th yl)-4,5-d ih yd r o-oxa zole-4-yl]-p h en -
yl-m eth a n ol (4c). The crude product was purified through
column chromatography on silica gel (eluent: PE/ethyl acetate/
Et3N ) 3/1/1) to give 4c (63%) as a colorless oil: [R]D +27.4 (c
1.0, CHCl3); IR (Nujol; cm-1) 3350, 1641; 1H NMR (300 MHz,
CDCl3) δ (ppm) 3.44 (br, 1H), 4.18-4.24 (m, 1H), 4.29-4.35
(m, 1H), 4.68-4.76 (m, 2H), 7.38-7.63 (m, 9H), 7.88-8.12 (m,
3H), 9.14 (d, J ) 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 68.5, 73.5, 76.9, 124. 2, 124.6, 126.2, 126.3, 127.1, 127.3,
128.1, 128.3, 128.5, 129.2, 131.0, 132.2, 133.7, 140.1, 165.4;
MS(CI): 304 (M + H+), 272 (M - OH - N), 255 (M - H2O -
CH2O), 196 (M - PhCHOH), 155 (C10H7CO+), 107 (PhCHOH+);
HRMS calcd for C20H17NO2 303.1259, found 303.1263.
[(S,S)-2-Ben zyl-4,5-dih ydr o-oxazole-4-yl]-ph en yl-m eth a-
n ol (4d ). The residue was recrystallized from a solvent
mixture of PE and ethyl acetate to give 4d (51%) as white
crystals: mp 116-119 °C; [R]D +76.0 (c 1.0, CHCl3); IR (Nujol,
cm-1) 3220, 1660; 1H NMR (300 MHz, CDCl3) δ (ppm) 3.38
(br, 1H) 3.66 (s, 2H), 3.97-4.03 (m, 1H), 4.08-4.14 (m, 1H),
4.37-4.45 (m, 1H), 4.53 (d, J ) 7.8 Hz, 1H), 7.18-7.39 (m,
10H); 13C NMR (75 MHz, CDCl3) δ (ppm) 34.7, 69.4, 72.3, 76.6,
127.0, 128.1, 128.5, 128.6, 128.8, 128.9, 129.3, 134.7, 139.9,
168.0; MS (CI) 267 (M+), 161 (M - PhCHOH), 118 (PhCH2-
CNH+), 91 (PhCH2+). Anal. Calcd for C17H17NO2: C, 76.38; H,
6.41; N, 5.24. Found: C, 76.07; H, 6.48; N, 5.24.
P r ep a r a tion of (1S,2S)-2-(4′-Br om oben zoyla m in o)-1-
p h en yl-p r op a n e-1,3-d iol (6g). To a solution of (1S,2S)-2-
amino-1-phenyl-propanediol (501 mg, 3.0 mmol) in THF (25
mL) and anhydrous triethylamine (10 mL) was added 4-bro-
mobenzoyl chloride (658 mg, 3 mmol). After the reaction
mixture was stirred at room temperature for 2 h, removal of
the solvent under reduced pressure provided a white solid.
Washing the solid with water and drying gave 6g (1.04 g) in
99% yield: mp 213-215 °C; 1H NMR (300 MHz, DMSO-d6) δ
(ppm) 3.54-3.61 (m, 2H), 4.13-4.17 (m, 1H), 4.75-4.79 (m,
1H), 4.89-4.91 (m, 1H), 5.48-5.50 (d, J ) 5.1 Hz, 1H), 7.15-
7.34 (m, 5H), 7.62-7.72 (m, 4H), 7.92 (d, J ) 8.7 Hz, 1H); 13
C
NMR (300 MHz, DMSO-d6) δ (ppm) 57.7, 60.8, 70.9, 125.1,
126.6, 127.1, 128.1, 129.8, 131.5, 134.1, 143.8, 165.8; MS (CI)
m/e 183 (79BrPhCO+, 100%), 185 (81BrPhCO+, 100%), 225, 227,
242 (M - PhCHOH - 1), 244, 350 (M + 1), 352 (M + 1). Anal.
Calcd for C16H16BrNO3: C, 54.87; H, 4.60; N, 4.00. Found: C,
54.74; H, 4.58; N, 4.00.
[(S,S)-2-Naph th ylm eth yl-4,5-dih ydr o-oxazole-4-yl]-ph en -
yl-m eth a n ol (4e). The residue was purified through column
chromatography on silica gel (eluent: PE/ethyl acetate/Et3N
) 2/1/1) to give 4e (51%) as white crystals: mp 111-114 °C;
[R]D +60.7 (c 1.0, CHCl3); IR (Nujol) cm-1 3250, 1644; 1H NMR
(300 MHz, CDCl3) δ (ppm) 3.93-3.99 (m, 1H), 4.04-4.10 (m,
3H), 4.35-4.43 (m, 1H), 4.48 (d, J ) 7.8 Hz, 1H), 7.28-7.56
(m, 9H), 7.79-7.89 (m, 2H), 8.12-8.15 (d, J ) 7.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ (ppm) 32.5, 69.5, 72.4, 76.5, 123.8,
125.4, 125.8, 126.3, 126.9, 127.5, 128.0, 128.1, 128.4, 128.7,
131.0, 132.0, 133.8, 139.9, 168.0; MS (CI) 317 (M+), 299 (M -
H2O), 211 (M + H - PhCHOH), 141 (NaphCH2+). Anal. Calcd
for C21H19NO2: C, 79.47; H, 6.03; N, 4.41. Found: C, 79.25;
H, 6.17; N, 4.41.
P r ep a r a tion of (1S,2S)-2-(4′-Meth ylben zoyla m in o)-1-
p h en yl-p r op a n e-1,3-d iol (6j). To a solution of (1S,2S)-2-
amino-1-phenyl-propanediol (501 mg, 3.0 mmol) in THF (25
mL) and anhydrous triethylamine (10 mL) was added 4-me-
thylbenzoyl chloride (464 mg, 3.0 mmol). After the reaction
mixture was stirred at room temperature for 2 h, removal of
the solvent under reduced pressure provided a white solid.
Washing the solid with water and drying gave 6j (824 mg) in
96% yield: mp 201-202 °C; 1H NMR (300 MHz, DMSO-d6) δ
(ppm) 2.33 (s, 3H, CH3), 3.34-3.39 (m, 1H), 3.56-3.64 (m, 1H),
4.15-4.18 (m, 1H), 4.75-4.79 (m, 1H), 4.92-4.95 (d, J ) 5.4
Hz, 1H), 7.16-7.35 (m, 7H), 7.66 (d, J ) 7.8 Hz, 2H); 13C NMR
(75 MHz, DMSO-d6) δ (ppm) 21.3, 57.5, 60.8, 70.7, 126.5, 127.1,
127.6, 128.1, 129.1, 132.2, 141.2, 143.9, 166.5; MS (CI) 119,
161 (100%), 178 (M - PhCHOH, 31%), 286 (M + 1). Anal.
Calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C,
71.30; H, 6.76; N, 5.08.
[(S ,S )-2-(2′-Br om op h e n yl-4,5-d ih yd r o-oxa zole -4-yl)-
p h en yl-m eth a n ol (4f): yield 60%; mp 79.3-81.9 °C; [R]25
D
+70.6 (c 1.0, CDCl3); IR (Nujol) cm-1 3390 (OH), 1643 (CdN);
1H NMR (300 MHz, CDCl3) δ (ppm) 2.7 (br, 1H), 4.23-4.38
(m, 2H), 4.61-4.71 (m, 2H), 7.28-7.49 (m, 7H), 7.67-7.73 (m,
2H); 13C NMR (300 MHz, CDCl3) δ (ppm) 69.5, 72.9, 76.5,
121.9, 127.0, 127.1, 128.2, 128.5, 129.2, 131.2, 131.8, 133.8,
139.9, 164.7; MS(CI) 77, 79, 107, 146, 183 (79BrPhCO+, 100%),
185 (81BrPhCO+, 100%), 225 (M + 1 - PhCHOH, 59%), 227
(M + 1 - PhCHOH, 60%), 332 (M + H+), 334 (M + H+). Anal.
Calcd for C16H14BrNO2: C, 57.85; H, 4.25; N, 4.22. Found: C,
57.63; H, 4.46; N, 4.41.
P r ep a r a tion a n d Ch a r a cter iza tion of [(S,S)-2-P h en yl-
4,5-d ih yd r o-oxa zole-4-yl]-p h en yl-m eth a n ol (4a ). To a so-
lution of 6a (1.626 g, 6.0 mmol) in anhydrous dichloromethane
(30 mL) and Et3N (30 mL) was added p-toluenesulfonyl
chloride (1.261 g, 6.0 mmol). After the reaction mixture was
refluxed for 24 h, the solvent was evaporated. To the residue
was added water (50 mL), and the aqueous layer was extracted
with dichloromethane (3 × 30 mL). The combined organic layer
was washed with brine and dried over anhydrous Na2SO4.
After removal of the solvent, the residue was purified through
column chromatography on silica gel (eluent: PE/ethyl acetate/
Et3N ) 3/1/1) to give 4a (1.221 g, 4.8 mmol, 80%) as a white
Cr ysta l Da ta : C16H14BrNO2, MW ) 332.19, monoclinic,
space group P21, a ) 12.624(2), b ) 8.817(2), c ) 14.573(2) Å,
R ) 90°, â ) 113.26(1)°, γ ) 90°, U ) 1490.2(5) Å3, T ) 295(2)
K, Z ) 4, Dc ) 1.481 mg/m3, µ ) 2.759 mm-1, λ ) 0.71073 Å,
F(000) 672, crystal size 0.48 × 0.48 × 0.44 mm, 4711 reflections
collected, 4064 independent reflection [Rint ) 0.0159]; refine-
ment method, full-matrix least-squares on F2; goodness-of-fit
on F2 ) 0.879, final R indices [I > 2σ(I)] R1 ) 0.0362, wR2
0.0669.
)
solid: mp 94-97 °C; [R]D +77.7 (c 1.0, CHCl3); IR (Nujol, cm-1
)
[(S ,S )-2-(4′-Br om op h e n yl-4,5-d ih yd r o-oxa zole -4-yl)-
3390, 1643; 1H NMR (300 MHz, CDCl3) δ (ppm) 3.50 (br, 1H),
4.12-4.19 (m, 1H), 4.26-4.32 (m, 1H), 4.56-4.60 (m, 2H),
7.28-7.46 (m, 8H), 7.98-8.01 (m, 2H); 13C NMR (75 MHz,
p h en yl-m eth a n ol (4g): yield 65%; mp 150.4-152.4 °C; [R]25
D
+49.8 (c 1.0, CDCl3); IR (Nujol) cm-1 3200, 1640; 1H NMR (300
MHz, CDCl3) δ (ppm) 3.50 (br, 1H), 4.15-4.27 (m, 2H), 4.54-
J . Org. Chem, Vol. 68, No. 11, 2003 4327

Zhang et al.
4.58 (m, 2H), 7.28-7.46 (m, 5H), 7.54-7.57 (d, J ) 8.4 Hz,
2H), 7.82-7.85 (d, J ) 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ (ppm) 69.5, 73.0, 76.5, 127.0, 128.2, 128.5, 129.9, 131.6, 139.9,
164.5; MS (CI) 77, 79, 107, 146, 183 (79BrPhCO+, 100%), 185
(81BrPhCO+, 100%), 224 (M - PhCHOH, 54%), 225 (M + 1 -
PhCHOH, 96%), 226 (M - PhCHOH, 62%), 227 (M + 1 -
PhCHOH, 93%), 332 (M + H+), 334 (M + H+). Anal. Calcd for
(eluent: EtOAc/PE ) 1/3) to give 4l (44 mg) as white crystals:
yield 84%; mp 163-165 °C; [R]25 -28.9 (c 10.5, CHCl3); IR
D
(Nujol) cm-1 3390 (OH), 1643 (CdN); 1H NMR (300 MHz,
CDCl3) δ (ppm) 3.13-3.21 (br, 1H), 4.16-4.22 (m, 1H), 4.44-
4.49 (m, 1H), 4.64-4.71 (m, 1H), 5.32 (d, J ) 2.8 Hz, 1H),
7.29-7.53 (m, 8H), 7.92-7.95 (m, 2H); 13C NMR (75 MHz,
CHCl3) δ (ppm) 67.1, 72.2, 72.6, 125.6, 125.9, 126.9, 127.3,
127.5, 128.1, 128.2, 128.3, 128.4, 128.6, 131.4, 140.4, 166.0;
MS(CI) 254 (M + H+), 236 (M - OH), 147 (M + H - PhCHOH),
105 (PhCO+); HRMS calcd for [C16H13NO]+ 235.0997, found
235.0996.
C
16H14BrNO2: C, 57.85; H, 4.25; N, 4.22. Found: C, 57.61; H,
4.50; N, 4.35.
[(S,S)-2-(2′-Met h ylp h en yl-4,5-d ih yd r o-oxa zole-4-yl)-
p h en yl-m eth a n ol (4h ): yield 50%; [R]25D +52.7 (c 0.8, CDCl3);
IR (Nujol) cm-1 3242-3374, 1643; 1H NMR (300 MHz, CDCl3)
δ (ppm) 2.60 (s, 3H), 3.93 (br, 1H), 4.11-4.25 (m, 2H), 4.59-
4.63 (m, 2H), 7.23-7.47 (m, 7H), 7.83(d, 1H); 13C NMR (75
MHz, CDCl3) δ (ppm) 21.7, 68.6, 73.2, 125.6, 126.8, 127.1,
128.1, 128.2, 128.4, 129.9, 130.8, 131.2, 138.8, 140.1, 165.9;
MS (CI) 119 (PhCH(OH)C+, 100%); 160 (M - PhCHOH, 90%);
161 (M + 1 - PhCHOH, 75%), 268 (M + H+). Anal. Calcd for
[(S,S)-2-Isop r op yl-4,5-d ih yd r o-oxa zole-4-yl]-p h en yl-
m et h a n ol (4b). To a solution of (1S,2S)-2-amino-1-phenyl-
propanediol (0.167 g, 1.0 mmol) in anhydrous THF (10 mL)
were added Et3N (1.5 mL) and isobutylryl chloride (0.678 g,
3.0 mmol). After the reaction mixture was stirred at room
temperature for 16 h, the solvent was evaporated under
reduced pressure. The residue was dissolved in anhydrous
dichloromethane (10 mL) and Et3N (10 mL). To the solution
was added p-toluenesulfonyl chloride (0.191 g, 1 mmol). After
the reaction mixture was refluxed for 24 h, the solvent was
evaporated. To the residue was added water (20 mL), and the
aqueous layer was extracted with dichloromethane (3 × 10
mL). The combined organic layer was washed with brine and
dried over anhydrous Na2SO4. After removal of the solvent,
the residue was purified through column chromatography on
silica gel (eluent: PE/ethyl acetate/Et3N ) 4/1/1) to give 4b
C
17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.34; H,
6.44; N, 5.36.
[(S,S)-2-(3′-Met h ylp h en yl-4,5-d ih yd r o-oxa zole-4-yl)-
p h en yl-m eth a n ol (4i): yield 53%; [R]25D +83.1 (c 0.6, CDCl3);
IR (Nujol) cm-1 3250-3351, 1644; 1H NMR (300 MHz, CDCl3)
δ (ppm) 2.34 (s, 3H), 4.10-4.23 (m, 2H), 4.57-4.65 (m, 2H),
4.80 (br, 1H), 7.24-7.47 (m, 7H), 7.77-7.84 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 21.1, 69.3, 72.9, 125.5,127.1, 127.2,
127.9, 128,2, 128.4, 129.0, 132.3, 137.9, 140.0, 165.5; MS (CI)
119 (PhCH(OH)C+, 88%); 160 (M - PhCHOH, 76%); 161 (M
(0.176 g, 0.8 mmol, 80%) as white crystals: mp 65-68 °C; [R]25
D
+ 1 - PhCHOH, 100%), 268 (M + H+). Anal. Calcd for C17H17
-
+89.7 (c 1.0, CHCl3); IR (Nujol) cm-1 3175, 1652; 1H NMR (300
MHz, CDCl3) δ (ppm) 1.18-1.21 (m, 6H), 2.55-2.64 (m, 1H),
3.96-4.01 (m, 1H), 4.05-4.11 (m, 1H), 4.31-4.39 (m, 1H), 4.49
(d, J ) 7.8 Hz, 1H), 7.28-7.43 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ (ppm) 19.6, 28.1, 68.9, 72.1, 76.5, 127.0, 128.1, 128.4,
139.9, 173.7; MS (CI) 220 (M + H+), 113 (M - PhCHOH), 43
(iPr+); HRMS calcd for C13H17NO2 219.1259, found 219.1252.
NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.06; H, 6.60; N,
5.31.
[(S,S)-2-(4′-Met h ylp h en yl-4,5-d ih yd r o-oxa zole-4-yl)-
p h en yl-m eth a n ol (4j): yield 61%; mp 105.8-106.7 °C; [R]25
D
+67.5 (c 1.0, CDCl3); IR (Nujol) cm-1 3189, 1642; 1H NMR (300
MHz, CDCl3) δ (ppm) 2.41 (s, 3H), 4.10-4.26 (m, 2H), 4.51-
4.60 (m, 2H), 7.20-7.44 (m, 7H), 7.87 (d, J ) 8.1 Hz, 1H); 13
C
Gen er a l P r oced u r e for th e En a n tioselective Ad d ition
of Dieth ylzin c to N-(Dip h en ylp h osp h in oyl) Im in es. N-
(Diphenylphosphinoyl) benzalimine (9a ) (30.5 mg, 0.1 mmol)
and oxazoline 4a (25.3 mg, 0.1 mmol) were dissolved in dry
toluene (1.5 mL) under argon. To the mixture was added Et2-
Zn in hexane (1 M, 0.5 mL, 0.5 mmol) at room temperature.
After the mixture was stirred for 48 h, the reaction was
quenched with saturated aqueous ammonium chloride and 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 through column chromatography on silica gel to give
N-(1-phenylpropyl)-P,P-diphenylphosphinoylamide (10a ) (25.8
mg, 0.077 mmol, 77%) as a white solid: mp 155-157 °C; IR
NMR (300 MHz, CDCl3) δ (ppm) 21.5, 69.3, 72.9, 76.6, 124.4,
127.0, 128.1, 128.3, 128.5, 129.0, 140.2, 142.0, 165.4; MS(CI)
91, 105 (PhCO+), 119, 132, 160 (M - PhCHOH, 100%), 161,
250 (M - OH), 268 (M + H+). Anal. Calcd for C17H17NO2: C,
76.38; H, 6.41; N 5.24. Found: C, 76.16, H 6.42, N 5.40.
Cr ysta l Da ta : C17H17NO2, MW ) 267.32, Monoclinic, space
group P21, a ) 7.778(2), b ) 9.602(3), c ) 9.977(2) Å, R ) 90°,
â ) 97.20(2)°, γ ) 90°, U ) 739.3(3) Å3, T ) 295(2) K, Z ) 2,
Dc ) 1.201 mg/m3, µ ) 0.079 mm-1, λ ) 0.71073 Å, F(000) 284,
crystal size 0.58 × 0.44 × 0.20 mm, 1996 reflections collected,
1798 independent reflection [Rint ) 0.0113]; refinement method,
full-matrix least-squares on F2; goodness-of-fit on F2 ) 0.831,
final R indices [I > 2σ(I)] R1 ) 0.0376, wR2 ) 0.0746.
1
(Nujol) cm-1 3135, 1188; H NMR (300 MHz, CDCl3) δ (ppm)
[(S,S)-2-(4′-Meth oxylp h en yl-4,5-d ih yd r o-oxa zole-4-yl)-
p h en yl-m eth a n ol (4k ): yield 56%; mp 85.5-86.2 °C; [R]25
0.80 (t, J ) 7.4 Hz, 3H), 1.80-1.95 (m, 1H), 1.98-2.10 (m, 1H),
3.32 (m, 1H), 4.10 (m, 1H), 7.15-7.46 (m, 11H), 7.78-7.89 (m,
4H); 13C NMR (75 MHz, CDCl3) δ (ppm) 10.5, 32.5, 57.1, 125.0,
126.4, 126.6, 127.0, 128.1, 128.3, 128.4, 128.5, 131.6, 131.7,
131.8, 132.4, 132.6, 143.4; MS (CI) 334 (M - H), 306 (M -
CH2CH3), 258 (M - Ph), 216 (Ph2PONH+), 201 (Ph2PO+). The
(S)-isomer (major product) was obtained in 91% ee as deter-
mined by HPLC (Chiracel AD column, hexane/propan-2-ol )
80/20; flow rate ) 1 mL/min; (R)-isomer, tR ) 13.17 min; (S)-
isomer, tR ) 17.82 min).
D
+51.0 (c 1.0, CDCl3); IR (Nujol) cm-1 3192, 1638; 1H NMR (300
MHz, CDCl3) δ (ppm) 3.50 (br, 1H), 3.87 (s, 3H), 4.12-4.29
(m, 2H), 4.52-4.59 (m, 2H), 6.93 (d, J ) 7.8 Hz, 2H), 7.27-
7.47 (m, 5H), 7.94 (d, J ) 7.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ (ppm) 55.2, 69.3, 72.8, 113.6, 119.6, 127.0, 128.0,
128.4, 130.1, 140.3, 162.2, 165.1; MS (CI) 177 (M + 1 -
PhCHOH, 100%), 284 (M + H+). Anal. Calcd for C17H17NO3:
C, 72.07; H, 6.05; N, 4.94. Found: C, 71.84; H, 6.12; N, 5.21.
P r ep a r a tion a n d Ch a r a cter iza tion of [(R,S)-2-P h en yl-
4,5-d ih yd r o-oxa zole-4-yl]-p h en yl-m eth a n ol (4l). To a solu-
tion of triphenylphosphine (314 mg, 1.2 mmol), 4-nitrobenzoic
acid (200 mg, 1.2 mmol), and DEAD (209 mg, 1.2 mmol) in
THF (5 mL) was added a solution of [(S,S)-2-phenyl-4,5-
dihydro-oxazole-4-yl]-phenyl-methanol 4a (253 mg, 1.0 mmol)
in THF (5 mL) dropwise. After the reaction mixture was
refluxed for 10 h, removal of the solvent and purification of
the residue through a column chromatography (eluent: EtOAc/
PE ) 1/4) gave 8 in 21% yield as a colorless oil. Intermediate
8 was dissolved in the solution of K2CO3 in CH3OH and stirred
overnignt at room temperature. After removal of the solvent,
the residue was purified through column chromatography
N-[1-(4′-Ch lor op h en yl)p r op yl]-P ,P -d ip h en ylp h osp h i-
n oyla m id e (10b). This compound (30.3 mg, 0.082 mmol, 82%)
was obtained as a white solid: mp 184-185 °C; IR (Nujol) cm-1
1
3220, 1184; H NMR (300 MHz, CDCl3) δ (ppm) 0.80 (t, J )
7.4 Hz, 3H), 1.82 (m, 1H), 1.98 (m, 1H), 3.36 (m, 1H), 4.07 (m,
1H), 7.08-7.48 (m, 10H), 7.70-7.90 (m, 4H); 13C NMR (75
MHz, CDCl3) δ (ppm) 10.5, 32.3, 56.4, 127.9, 128.1, 128.2,
128.3, 128.4, 128.5, 128.7, 131.7, 131.8, 132.0, 132.3, 132.4,
132.6, 132.7, 133.7, 142.0, 142.1; MS (CI) 369 (M+), 341 (M -
CH2dCH2), 259 (M + H - ClC6H4), 217 (Ph2PONH2+), 202
(Ph2POH+). Anal. Calcd for C21H21ClNOP: C, 68.20; H, 5.72;
N, 3.79; Cl, 9.59. Found: C, 68.29; H, 5.75; N, 3.69; Cl, 9.40.
4328 J . Org. Chem., Vol. 68, No. 11, 2003

Evaluation of Chiral Oxazolines
The (S)-isomer (major product) was obtained in 92% ee as
determined by HPLC (Chiracel AD column, hexane/propan-
2-ol ) 95/5; flow rate ) 1 mL/min; (R)-isomer, tR ) 9.87 min
and (S)-isomer, tR ) 11.15 min).
69.65; H, 5.84; N, 3.69. Found: C, 69.79; H, 5.90; N, 3.59. The
(S)-isomer (major product) was obtained in 90% ee as deter-
mined by HPLC (Chiracel AD column, hexane/propan-2-ol )
80/20; flow rate ) 1 mL/min; (R)-isomer, tR ) 11.05 min; (S)-
isomer, tR ) 17.59 min).
N-[1-(4-Br om op h en yl)p r op yl]-P ,P -d ip h en ylp h osp h i-
n oyla m id e (10c). This compound (34.4 mg, 0.083 mmol, 83%)
was obtained as a white solid: mp 174-176 °C; IR (Nujol) cm-1
N-[1-(4′-Met h ylp h en yl)p r op yl]-P ,P -d ip h en ylp h osp h i-
n oyla m id e (10f). This compound (25.0 mg, 0.072 mmol, 72%)
was obtained as a white solid: mp 158-159 °C; IR (Nujol) cm-1
1
3224, 1184; H NMR (300 MHz, CDCl3) δ (ppm) 0.78 (t, J )
1
7.2 Hz, 3H), 1.74-1.84 (m, 1H), 1.86-2.01 (m, 1H), 3.38 (m,
1H), 4.05 (m, 1H), 7.03 (d, 2H, J ) 7.8 Hz), 7.27-7.48 (m, 8H),
7.70-7.74 (m, 2H), 7.83-7.89 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ (ppm) 10.5, 32.3, 56.5, 120.7, 128.2, 128.3, 128.5,
130.8, 131.4, 131.7, 131.8, 132.3, 132.4, 132.5, 133.5, 142.5,
142.6; MS (CI) 415 (M+), 385 (M - CH2dCH2), 305 (M - Br -
CH2CH3), 212 (M - Ph2PO), 201 (Ph2PO+). Anal. Calcd for
3224, 1185; H NMR (300 MHz, CDCl3) δ (ppm) 0.78 (t, J )
7.4 Hz, 3H), 1.78-1.90 (m, 1H), 1.95-2.09 (m, 1H), 2.35 (s,
3H), 3.30-3.33 (m, 1H), 4.05-4.14 (m, 1H), 7.06 (d, J ) 8.1
Hz, 2H), 7.12 (d, J ) 8.1 Hz, 2H), 7.35-7.48 (m, 6H), 7.75-
7.89 (m, 4H); 13C NMR (75 MHz, CDCl3) δ (ppm) 10.5, 21.0,
32.4, 56.9, 126.3, 128.1, 128.3, 128.4, 129.1, 131.6, 131.7, 131.8,
132.4, 132.5, 132.6, 136.6, 140.4; MS (CI) 320 (M - CH2CH3),
201 (Ph2PO+), 148 (M - Ph2PO). Anal. Calcd for C22H24NOP:
C, 75.62; H, 6.92; N, 4.01. Found: C, 75.52; H, 6.89; N, 4.18.
The (S)-isomer (major product) was obtained in 93% ee as
determined by HPLC (Chiracel AD column, hexane/propan-
2-ol ) 92/8; flow rate ) 1 mL/min; (R)-isomer, tR ) 21.83 min;
(S)-isomer, tR ) 27.42 min).
C
21H21BrNOP: C, 60.88; H, 5.11; N, 3.38; Br, 19.29. Found:
C, 60.97; H, 5.16; N, 3.53; Br, 19.15. The (S)-isomer (major
product) was obtained in 90% ee as determined by HPLC
(Chiracel AD column, hexane/propan-2-ol ) 80/20; flow rate
) 1 mL/min; (R)-isomer, tR ) 11.12 min; (S)-isomer, tR ) 12.82
min).
N-[1-(4-Meth oxyp h en yl)p r op yl]-P ,P -d ip h en ylp h osp h i-
n oyla m id e (10d ). This compound (30.7 mg, 0.084 mmol, 84%)
was obtained as a white solid: mp 173-174 °C; IR (Nujol) cm-1
N-[1-(3-Met h ylp h en yl)p r op yl]-P ,P -d ip h en ylp h osp h i-
n oyla m id e (10g). This compound (23.8 mg, 0.068 mmol, 68%)
was obtained as a white solid: mp 133-134 °C; IR (Nujol) cm-1
1
3203, 1182; H NMR (300 MHz, CDCl3) δ (ppm) 0.78 (t, J )
1
3135, 1197; H NMR (300 MHz, CDCl3) δ (ppm) 0.78 (t, J )
7.4 Hz, 3H), 1.77-1.86 (m, 1H), 1.96-2.05 (m, 1H), 3.31 (m,
1H), 3.81 (s, 3H), 4.04-4.07 (m, 1H), 6.83 (d, J ) 8.7 Hz, 2H),
7.09 (d, J ) 8.7 Hz, 2H), 7.28-7.48 (m, 6H), 7.79-7.88 (m,
4H); 13C NMR (75 MHz, CDCl3) δ (ppm) 10.6, 32.3, 55.2, 56.6,
113.7, 127.5, 128.1, 128.2, 128.3, 128.5, 131.6, 131.7, 131.8,
132.4, 132.6, 135.5, 158.4; MS (CI) 365 (M+), 336 (M - CH2-
7.3 Hz, 3H), 1.79-1.91 (m, 1H), 1.95-2.06 (m, 1H), 2.32 (s,
3H), 3.30-3.33 (m, 1H), 4.02-4.09 (m, 1H), 6.92-7.07 (m, 3H),
7.20-7.27 (m, 1H), 7.35-7.48 (m, 6H), 7.77-7.88 (m, 4H); 13
C
NMR (75 MHz, CDCl3) δ (ppm) 10.5, 21.4, 32.3, 57.1, 123.4,
127.3, 127.7, 128.1, 128.2, 128.3, 128.4, 131.6, 131.7, 131.8,
132.5, 132.6, 137.9, 143.2, 143.3; MS (CI) 320 (M - CH2CH3),
258 (M - CH3C6H4), 201 (Ph2PO+), 148 (M - Ph2PO). Anal.
Calcd for C22H24NOP: C, 75.62; H, 6.92; N, 4.01. Found: C,
75.89; H, 6.92; N, 3.99. The (S)-isomer (major product) was
obtained in 93% ee as determined by HPLC (Chiracel AD
column, hexane/propan-2-ol ) 90: 10; flow rate ) 1 mL/min;
(R)-isomer, tR ) 10.96 min; (S)-isomer, tR ) 20.88 min).
CH3), 201 (Ph2PO+), 164 (M - Ph2PO). Anal. Calcd for C22H24
-
NO2P: C, 72.31; H, 6.62; N, 3.83. Found: C, 72.61; H, 6.64;
N, 3.72. The (S)-isomer (major product) was obtained in 90%
ee as determined by HPLC (Chiracel AD column, hexane/
propan-2-ol ) 80/20; flow rate ) 1 mL/min; (R)-isomer, tR
10.35 min; (S)-isomer, tR ) 17.59 min).
)
N -(1-P ip e r o n y lp r o p y l)-P ,P -d ip h e n y lp h o s p h in o y l-
a m id e (10e). This compound (28.4 mg, 0.075 mmol, 75%) was
obtained as a white solid: mp 149-150 °C; IR (Nujol) cm-1
Ack n ow led gm en t. We are grateful for financial
support from the National Natural Science Foundation
of China (20102005).
1
3227, 1192; H NMR (300 MHz, CDCl3) δ (ppm) 0.78 (t, J )
7.4 Hz, 3H), 1.73-1.85 (m, 1H), 1.91-2.05 (m, 1H), 3.25 (m,
1H), 4.02-4.04 (m, 1H), 5.94-5.95 (m, 2H), 6.55-6.59 (m, 1H),
6.69-6.71 (m, 2H), 7.35-7.48 (m, 6H), 7.75-7.95 (m, 4H); 13
C
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
new compounds 4a -l, 6a , 6c, 6d , 6f, 6g, 6j, 9e, 9f, 10e, and
10f. X-ray spectra of 4f and 4j. This material is available free
of charge via the Internet at http://pubs.acs.org.
NMR (75 MHz, CDCl3) δ (ppm) 10.5, 32.4, 56.9, 100.9, 106.7,
107.9, 119.9, 128.1, 128.2, 128.3, 128.4, 131.5, 131.6, 131.7,
131.8, 132.3, 132.4, 132.5, 134.0, 137.5, 146.4, 147.6; MS (CI)
379 (M+), 350 (M - CH2CH3), 216 (Ph2PONH+), 201 (Ph2PO+),
178 (M - Ph2PO); 137.4 (Ar). Anal. Calcd for C22H22NO3P: C,
J O0268862
J . Org. Chem, Vol. 68, No. 11, 2003 4329