Diastereopure Preparation of α-Benzotriazolyl 1-Azacycloalka[2,1-b] [1,3]-oxazines and their Application as Versatile Chiral Precursors

Article abstract of DOI:10.1055/s-2003-43353

A group of diastereopure α-benzotriazolyl 1-azacycloalka[2,1-b][1,3] oxazines were prepared from non-racemic Betti base and they were employed as the versatile precursors for the preparation of chiral ligands and chiral substituted azacyclics with signifi

Full text of DOI:10.1055/s-2003-43353

122
LETTER
Diastereopure Preparation of a-Benzotriazolyl 1-Azacycloalka[2,1-b][1,3]-
oxazines and their Application as Versatile Chiral Precursors
D
a
iastereopure Pre
p
u
aration of
a
-
B
enzotriaz
n
olyl 1-Azacy
o
cloalka[2,1-
b
][1,3]-oxaz
g
Department of Chemistry, Nanjing University, Nanjing 210093, P. R. China
b
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
Fax +86(10)62771149; E-mail: yfh@mail.tsinghua.edu.cn
Received 3 October 2003
Ph
Abstract: A group of diastereopure a-benzotriazolyl 1-azacyclo-
alka[2,1-b][1,3]oxazines were prepared from non-racemic Betti
base and they were employed as the versatile precursors for the
preparation of chiral ligands and chiral substituted azacyclics with
significant advantages in the stereoselectivity.
OHC(CH2)mCHO, BtH
m = 2,3
O α' N α Bt
R-1
( )
n
3a n = 1; 3b n = 2
1-Azacycloalka[2,1-b][1,3]oxazole
Key words: Betti base, chiral [1,3]oxazines, chiral ligands, chiral
substituted azacyclics
Scheme 1
Although a number of chiral amino-hydroxy compounds
have been used as excellent ligands in the metallic ion cat-
alyzed asymmetric reactions,1 only a few of them could be
employed as chiral auxiliaries, such as 2-phenylglycinol
(1)2–4 and 2-(1-aminoethyl)phenol (2)5 (Figure 1), thanks
to their ability to dissociate the benzyl residues from the
products under a variety of conditions.
derived from them.6 This unusual phenomenon may result
from the fact that Betti base normally is not stable and
reversed Mannich reaction occurs spontaneously in the
usage and storage.
R NH2
OH
NH2
S
OH
Ph
NH2
HO
NH2
OH
S-4
Figure 2
R-4
R-1
Figure 1
S-2
In our recent work, non-racemic Betti base was used sta-
bly and conveniently as its salt of tartaric acid.7 Herein,
we report a diastereopure preparation of a-benzotriazolyl
1-azacycloalka[2,1-b][1,3]oxazines (5a–c) derived from
S-4, as well as their application as a group of newly chiral
precursors to the preparation of chiral ligands and chiral
azacyclics.
Recently, Katritzky reported an elegant method by using
R-(–)-2-phenylglycinol (R-1) as an auxiliary to synthesize
chiral substituted azacyclics as well as structurally related
natural products.3 As illustrated in Scheme 1, its key strat-
egy is to construct a-benzotriazolyl 1-azacycloalka[2,1-
b][1,3]oxazole (3) by a condensation between R-1 and a
dial in the presence of BtH (benzotriazole), followed by
an alkylation at the newly formed chiral carbon (a- or a¢-
positions) separately. However, some limitations for this
method have been observed. For example, 3b cannot be
obtained as a single diastereoisomer and its alkylation suf-
fered from low yields and less stereoselectivity.
Following Katritzky’s procedure, a mixture of S-4 [as a
salt of L-(+)-tartaric acid], pentane-1,5-dial and BtH in
CH2Cl2 was stirred at 0 °C for 5 hours. As expected, the
diastereopure a-benzotriazolyl 1-piperido[2,1-b][1,3]-
oxazine (5b) was obtained in 91% yield (Scheme 2). Its
diastereopurity was confirmed by the benzyl proton as a
singlet peak at d = 5.28 ppm in the 1H NMR spectroscopy
and the two newly formed chiral carbons are R-configura-
tions deduced from its single crystal X-ray diffraction
analysis. Similarly, replacement of pentane-1,5-dial by
butane-1,4-dial and hexane-1,6-dial, the five- and seven-
membered azacyclic analogues 5a and 5c were obtained
respectively in high yields (93% and 91%) and diastereo-
seletivities.
Betti base contains a 1,3-benzylamino-hydroxy skeleton
and its enantiomers (S-4 or R-4) (Figure 2) should be ex-
cellent chiral auxiliaries. To our surprise, none of them
has been used for this purpose and even most of the report-
ed chiral N-alkylated derivatives of Betti base did not
SYNLETT 2004, No. 1, pp 0122–0124
0
5.
0
1.
2
0
0
4
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43353; Art ID: U20603ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diastereopure Preparation of a-Benzotriazolyl 1-Azacycloalka[2,1-b][1,3]-oxazines
123
Bt
Table 1 Reductions of Compounds 8a–e with LiAlH4
α
( )
n
O
O
OCH(CH2)mCHO
BtH, –5 to 0 °C, 5 h
NH2
α'
N
HO
.
8,9
a
Ar
Yield of 8 (%)
Yield of 9 (%)
OH
OH
OH
O
m = 2,3,4
91-93%
C6H5
84
77
81
73
85
86
85
84
83
92
HO
b
4-MeC6H4
4-ClC6H4
4-PhC6H4
1-Naphthyl
5a–c n = 1,2,3
1-Azacycloalka [2,1-b][1,3]oxazine
S-4·L-(+)-Tartaric Acid
c
Scheme 2
d
e
The oxazines 5a–c have completely different structures
and stereochemistry compared to oxazoles 3a,b. We ob-
served that the C-O bond in a¢-position of oxazine 5 is
more stable than that of oxazole 3 probably because its
oxygen atom comes from the phenol. Thus, a selective
cleavage of C-Bt bond was achieved by treatment of
5a–c with NaBH3CN in CH2Cl2–MeOH at room tempera-
ture for 4–6 hours and the corresponding 6a–c were ob-
tained in 72–83% yields (Scheme 3). However, both C-Bt
and C-O bonds were cut clearly via LiAlH4 within half
hour at 0 °C to afford 7a–c in high yields (89–94%),
which have been proved to be excellent chiral ligands in
the asymmetric addition of ZnEt2 to aldehydes.7 The im-
proved procedures are particularly suitable for the bulky
synthesis of 6a–c and 7a–c.
figurations of the chiral carbons were assigned by the
single crystal X-ray diffraction analysis of 10a. Hydro-
genolysis of 10a–f afforded corresponding chiral 2-alkyl-
piperidines including the natural product R-(–)-coniine
(11c). Since the similar compounds prepared by the alkyl-
ation of 3b suffered seriously from the low yields and
lower distereoselectivities,3b our procedure afforded a
valuable alternative to the existed methods.
R
RMgBr, Et2O
N
hydrogenolysis
r.t., 30 min
81–91%
6b
OH
93–97%
R
N
H
α
n
NaBH3CN
n
10a–f
11a–f
CH2Cl2-MeOH
r.t., 4–6 h
α'
LiAlH4, Et2O
–5 to 0 °C, 0.5 h
N
N
Scheme 5
Table 2 Hydrogenolysis of Compounds 10a–f
O
OH
89–94%
72–83%
5a–c
6a–c n = 1,2,3
7a–c n = 1,2,3
10,11
R
Yield of 10 (%) Yield of 11 (%)
Scheme 3
a
b
c
d
e
f
Me
85
81
81
91
92
86
93
By using compound 5b as a model, the arylation at its a-
position was carried out by treatment it with ArMgBr to
give a series of diastereopure compounds 8a–e in good
yields. Although the products are consistent with that of
3b, the current procedure can be performed under very
mild conditions (Scheme 4, Table 1) rather than at –78 °C
for 12 hours.3b The arylated carbons were assigned as R-
configurations deduced from the single crystal X-ray
diffraction analysis of 8e. Reductions of 8a–e via LiAlH4
yielded a group of highly hindered 1,3-amino-phenols
9a–e, which could serve as potential chiral ligands in the
catalytic asymmetric reactions.
Et
94
n-Pr
94
n-C12H25
CH2=CHCH2
Bn
97
93 (11c)
96
In conclusion, a group of diastereopure a-benzotriazolyl
1-azacycloalka[2,1-b][1,3]oxazines 5a–c were prepared
from non-racemic Betti base and they were employed as
versatile chiral precursors for the preparation of chiral
ligands and chiral azacyclics with significant advantage in
the stereoselectivity. This may result from the fact that an
unique four-atom plane defined by C1 and C2 on the
naphthalene as well as the attached carbon and oxygen oc-
curs in 5a–c, which keeps each molecule in a very rigid
conformation.
Ar
Ar
R
ArMgBr, Et2O
–5 to 0 °C, 2–3 h
LiAlH4, Et2O
0 °C, 0.5 h
N
R
N
S
5b
O
OH
84–92%
73–85%
8a–e
9a–e
Scheme 4
Acknowledgment
In agreement with our expectation, the alkylation at the a¢-
position in 6b with RMgBr yielded highly diastereopure
10a–f in satisfactory yields (Scheme 5, Table 2). The con-
We are grateful to the National Natural Science Foundation of
China for financial support.
Synlett 2004, No. 1, 122–124 © Thieme Stuttgart · New York

124
X. Xu et al.
LETTER
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Synlett 2004, No. 1, 122–124 © Thieme Stuttgart · New York