Direct asymmetric synthesis of oxazolines from olefins using a chiral nitridomanganese complex: A novel three-component coupling leading to chiral oxazolines

Article abstract of DOI:10.1016/S0040-4039(01)01963-3

A new synthetic method for chiral oxazolines has been developed by N1 unit transfer to olefins using a chiral nitridomanganese complex. When trans-disubstituted styrenes were treated with chiral complex 1 in the presence of an acid chloride, oxazolines we

Full text of DOI:10.1016/S0040-4039(01)01963-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9019–9022
Direct asymmetric synthesis of oxazolines from olefins using a
chiral nitridomanganese complex: a novel three-component
coupling leading to chiral oxazolines
Satoshi Minakata, Masaaki Nishimura, Toru Takahashi, Yoji Oderaotoshi and Mitsuo Komatsu*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita,
Osaka 565-0871, Japan
Received 2 October 2001; accepted 18 October 2001
Abstract—A new synthetic method for chiral oxazolines has been developed by N1 unit transfer to olefins using a chiral
nitridomanganese complex. When trans-disubstituted styrenes were treated with chiral complex 1 in the presence of an acid
chloride, oxazolines were obtained with high enantioselectivities (up to 92% ee). Furthermore, the produced oxazolines could be
easily converted into b-amino alcohols, which are ephedrine derivatives. © 2001 Elsevier Science Ltd. All rights reserved.
It is well known that optically active oxazolines are
highly versatile five-membered heterocycles. The oxazo-
lines exist in a variety of natural products and biologi-
cally active compounds,1,2a and they can easily be
converted into optically active b-amino alcohols which
are useful synthetic intermediates.2,3 It has also been
revealed in the last decade that they act as potential
chiral ligands for asymmetric synthesis.4 In general, the
synthesis of chiral oxazolines from natural amino acids
involves several steps.2,5 Although natural amino acids
are readily available chiral sources, their use causes
limitations in the absolute configuration and the diver-
sity of substituents on the formed oxazoline ring.
Reagent-controlled synthesis of optically active oxazoli-
nes is a useful method, but only a few examples are
reported to date.6 While an alternative method for the
synthesis of achiral oxazolines from olefins and N-acyl
nitrenes has been reported, the reaction of photochemi-
cally or thermally generated N-acyl nitrenes with olefins
suffers from the problem that a variety of by-products
are also formed.7 Recently, we reported a unique nitro-
gen source, a chiral nitridomanganese complex (Fig. 1),
for use in the asymmetric aziridination of styrene
derivatives and conjugated dienes, where p-toluenesul-
fonic anhydride (Ts2O) played an important role as an
activator of the complex to complete the reaction.8 On
the other hand, N-acyl aziridines are known to isomer-
ize to oxazolines.9,10 This situation prompted us to
investigate the direct construction of oxazolines using a
nitrido complex as the nitrogen source. We report here
the first asymmetric synthesis of 2-oxazolines from
olefins with a chiral nitrido complex in the presence of
acid halides, in which 2-oxazolines are selectively pro-
duced without the formation of N-acyl aziridines.
As mentioned above, activating reagents of nitrido
complexes often influence the structure of products in
the N1 unit transfer to olefins.8,11 Acid chlorides might
be potent candidates as activators for the reaction to
give N-acyl aziridines or 2-oxazolines.12 While a simple
olefin, styrene was employed in the reaction of the
nitridomanganese complex 1 with benzoyl chloride as
an initial example, only a small amount of the corre-
sponding oxazoline was obtained, along with b-
chloroamide derivative. When trans-b-methylstyrene
was treated with the chiral nitridomanganese complex 1
in methylene chloride at room temperature for 48 h in
H
H
N
N
O
N
O
Mn
Keywords: asymmetric synthesis; chiral oxazolines; nitridomanganese
complex; olefins.
(R,R)-complex 1
* Corresponding author. Fax: (+81)6-6879-7402; e-mail: komatsu@
ap.chem.eng.osaka-u.ac.jp
Figure 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01963-3

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S. Minakata et al. / Tetrahedron Letters 42 (2001) 9019–9022
the presence of pyridine, pyridine N-oxide and benzoyl
chloride, 4-methyl-2,5-diphenyl-2-oxazoline (2a) was
obtained in 77% yield with 81% ee (Table 1). Although
N-aroyl nitrenes generally added to olefins to give
aziridines,7b oxazoline 2a was selectively produced with
no detectable formation of the corresponding N-benzoyl
aziridine in this reaction. Moreover, the reaction gave
exclusively trans-oxazoline with the retention of the
stereochemistry of the starting olefin. Thus, the reaction
conditions were optimized as follows. While the reaction
proceeded with good enantioselectivity (86% ee) at 0°C,
the chemical yield of 2 was moderate compared to the
yield at room temperature. In order to obtain a higher
chemical yield at 0°C, several additives were employed
inthereaction. TheadditionofasilversaltsuchasAgClO4
orAgBF4 wasfoundtodramaticallyimprovethechemical
yield with no significant loss in enantioselectivity. Fur-
thermore, a reaction conducted in the presence of AgBF4
but without pyridine gave the best result.13,14 The use of
the optimal conditions led to a better result, in terms of
the formation of the oxazoline from styrene (74%, 16%
ee).
To investigate the influence of an activator of complex
1 on the synthesis of oxazolines, several acid chlorides
were examined and the results are listed in Table 2. When
p-(trifluoromethyl)benzoyl chloride was employed in the
reaction, trans-b-methylstyrene was found to react
smoothly and the corresponding oxazoline was obtained
in 88% yield with 86% ee. Although it took a considerable
length of time to complete the reaction in the case of
p-methoxybenzoyl chloride, the yield and enantiomeric
excess of the produced oxazoline were the same as those
for the product from benzoyl chloride. These results
suggest that an electron-deficient substituent on the
phenyl ring of an acid chloride increases the rate of the
reaction. On the other hand, pivaloyl chloride, which is
an aliphatic acid chloride, was employed for the reaction
to give the 2-alkylated oxazoline in good yield with
excellent enantioselectivity, suggesting that the yields and
enantioselectivities of oxazolines were not influenced by
the nature of the acid chlorides.
Table 1. Asymmetric synthesis of oxazoline 2a from trans-
b-methylstyrene and complex 1a
Ph
(R,R)-complex 1, PhCOCl, additive
Me
pyridine, pyridine N-oxide
O
N
CH2Cl2, 48 h
Ph
Ph
Me
2a
The present reaction was successfully applied to the
synthesis of oxazolines from styrene derivatives, as shown
in Table 3. The reaction of trans-1-phenyl-1-pentene with
1 using benzoyl chloride afforded the desired oxazoline
in good yield with high enantioselectivity. trans-3-Phenyl-
1-methyl-2-butene and trans-b-cyclohexylstyrene were
transformed into the corresponding oxazolines in over
90% ee, respectively. In these reactions, the trans-oxazo-
lines were obtained as the sole products and cis-isomers
were not detected. Although the present reaction permit-
ted the conversion of cyclic olefins such as 1,2-dihy-
dronaphthalene and 1-phenylcyclohexene into the
polycyclic compounds, the yields and enantioselectivities
were moderate. As shown, the complex provides a highly
effective asymmetric environment for oxazoline synthesis
from trans-substituted styrene derivatives. The tendency
Entry
Additive
Temp. (°C)
Yield (%)
Ee (%)b,c
1
2
3
None
None
AgClO4
AgBF4
AgBF4
Rt
0
0
0
0
77
34
65
77
81
81
86
87
87
86
4
5d
a Reaction conditions: (R,R)-complex 1 (1 equiv.), PhCOCl (1.2
equiv.), additive (1.2 equiv.), pyridine (0.5 equiv.), pyridine N-oxide
(1.2 equiv.), trans-b-methylstyrene (10 equiv.).
b Enantiomeric excesses were determined by HPLC analysis using a
Daicel Chiralcel OD column.
c Absolute configurations were determined to be (4R,5R) by compari-
son of the measured optical rotations with reported values.3
d Reaction was run without pyridine.
Table 2. Effect of acid chlorides on the reaction of trans-b-methylstyrene with complex 1a
R1
(R,R)-complex 1, R1COCl
AgBF4, pyridine N-oxide
Me
O
N
CH2Cl2, 0 °C
Ph
Ph
Me
2a-d
Entry
R1
Time (h)
Oxazoline
Yield (%)
Ee (%)b
1
2
3
4
Ph
48
24
168
48
2a
2b
2c
2d
81
88
80
75
86c
86d
86d
85e
p-CF3C6H4-
p-MeOC6H4-
t-Bu
a Reaction conditions: (R,R)-complex 1 (1 equiv.), PhCOCl (1.2 equiv.), AgBF4 (1.2 equiv.), pyridine N-oxide (1.2 equiv.), trans-b-methylstyrene
(10 equiv.).
b Enantiomeric excesses were determined by HPLC analysis using a Daicel Chiralcel OD column or a Chiralpak AD column.
c Absolute configuration was determined as (4R,5R).3
d Absolute configurations were established as (4R,5R) by comparison of the measured optical rotations with that of 2a.
e Absolute configuration was determined as (4R,5R) using the corresponding amino alcohol derived from 2d.

S. Minakata et al. / Tetrahedron Letters 42 (2001) 9019–9022
9021
Table 3. Asymmetric synthesis of oxazolines from styrene
derivatives and complex 1a
The produced oxazolines could be easily converted into
b-amino alcohols. When oxazoline 2a was treated with
1.2N HCl at reflux for 30 h, norpseudoephedrine (5)
was obtained in good yield with the retention of the
stereochemistry (Eq. (2)).3 The hydrolysis of oxazoline
3c also took place under similar conditions to give the
non-natural b-amino alcohol 6 in high yield.
Entry Olefin
Time (h) Oxazoline Yield (%) Ee (%)b
Ph
n-Pr
88c
90c
92c
11d
32d
O
N
85
85
75
55
53e
1
2
3
4
5
24
24
36
72
48
Ph
Ph
Ph
Ph
Ph
n-Pr
3a
Ph
HO
Ph
NH2
R2
HCl (aq.)
O
N
i-Pr
reflux, 30 h
O
N
Ph
R2
2a: R2 = Me (86% ee)
3c: R2 = c-Hex (92% ee)
5: 93% yield (86% ee)
6: 88% yield (92% ee)
Ph
i-Pr
3b
Ph
c-Hex
(2)
O
N
In summary, we report on a reagent-controlled direct
synthesis of chiral 2-oxazolines from olefins using a
chiral nitridomanganese complex in the presence of acid
chlorides. The study represents the first example of a
[2+2+1] type asymmetric synthesis of oxazolines. The
reaction of trans-substituted styrene derivatives gave
rise to trans-2-oxazolines stereoselectively in good
yields with high enantioselectivity. A search for applica-
tions and the mechanism of the present reaction is
currently in progress.
Ph
c-Hex
3c
Ph
O
N
3d
Ph
O
N
Ph
Ph
H
3e
Acknowledgements
a
Reaction conditions: (R,R)-complex 1 (1 equiv.), PhCOCl (1.2
equiv.), AgBF4 (1.2 equiv.), pyridine N-oxide (1.2 equiv.), olefin (10
equiv.), CH2Cl2, 0°C.b Enantiomeric excesses were determined by
HPLC analysis using Daicel Chiralcel OD column or Chiralpak AD
column.c Absolute configurations were established as (4R,5R) by
comparison of the measured optical rotations with that of
2a.d Absolute configurations were not determined.e 1-Benzoylamino-
2-phenyl-2-cyclohexene was obtained in 11% yield.
This work was supported, in part, by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Science, Sports and Culture of Japan and The Naito
Foundation. We also acknowledge the Instrumental
Analysis Center, Faculty of Engineering, Osaka
University.
of a substituent effect on yields and enantiomeric
excesses in the reactions is similar to that in the azirid-
ination of these styrene derivatives using complex 1 and
Ts2O.8a
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(0.36 mmol) and pyridine N-oxide (0.36 mmol) in CH2Cl2
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