Diastereoselective synthesis of oxazolo[3,4-b]tetrahydroisoquinolin-3-ones via Lewis acid TMSOTf-mediated Pictet-Spengler reaction

Article abstract of DOI:10.1016/j.tetasy.2013.10.015

An alternative and efficient method to stereoselectively synthesize oxazolo[3,4-b]tetrahydroisoquinolin-3-ones via a Pictet-Spengler reaction promoted by Lewis acid TMSOTf from readily available (S)-4-benzyl-2- oxazolidinone with various aromatic, aliphat

Full text of DOI:10.1016/j.tetasy.2013.10.015

Tetrahedron: Asymmetry 24 (2013) 1591–1597
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective synthesis of oxazolo[3,4-b]
tetrahydroisoquinolin-3-ones via Lewis
acid TMSOTf-mediated Pictet–Spengler reaction
⇑
⇑
Zhenbei Zhang, Tong-Xin Liu , Qingfeng Liu, Zhiguo Zhang, Guisheng Zhang
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007,
PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 September 2013
Accepted 31 October 2013
An alternative and efficient method to stereoselectively synthesize oxazolo[3,4-b]tetrahydroisoquinolin-
3-ones via a Pictet–Spengler reaction promoted by Lewis acid TMSOTf from readily available (S)-4-ben-
zyl-2-oxazolidinone with various aromatic, aliphatic, and cyclic aldehydes under room temperature is
described.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
H2SO4, CF3SO3H, and CF3COOH, were reported by Tomioka et al.,
which provided the corresponding derivatives in
a more
Tetrahydroisoquinolines are important N-containing heterocy-
cles that are present in a variety of natural and synthetic therapeu-
tic products with a wide range of biological and pharmacological
activities.1 Among the various tetrahydroisoquinoline derivatives,
oxazolo[3,4-b]tetrahydroisoquinolin-3-ones have attracted special
attention. On the one hand, as analogues of strong antitumor
agents such as podophyllotoxin,2,3 many of them have been found
to exhibit potent cytotoxicity and inhibition to KB cells in vivo
against P-388 in mice4 and cells derived from human carcinoma
of the nasopharynx,5 as well as inhibitors of DNA topoisomerase
II.6 On the other hand, the transformation of these compounds into
b-amino alcohols through hydrolysis, means that not only can they
be used as useful intermediates in the synthesis of naturally occur-
ring alkaloids and synthetic biologically active molecules,1,7 but it
also allows them to be used as precursors of ligands,8 chiral auxil-
iaries,9 and catalysts10 in organic synthesis (Fig. 1).
straightforward and efficient manner.4,5,14 Katritzky developed a
benzotriazole methodology to stereospecifically synthesize oxazol-
o[3,4-b]tetrahydroisoquinolin-3-ones.15 In contrast with the above
methods, Katritzky’s method produced single diastereomers in two
steps, that is the PTSA-catalyzed intramolecular reaction of (S)-4-
benzyl-2-oxazolidinone with benzotriazole and diverse aldehydes,
followed by treating the formed benzotriazole Mannich intermedi-
ates with a Lewis acid, TiCl4 or AlCl3, to give the final products as
pure stereoisomers. In addition, another similar approach was also
established to obtain pure stereoisomers via the Lewis acid-treat-
ment of (phenylsulfonyl)alkyl oxazolidin-2-ones, which were gen-
erated from the reaction of (S)-4-benzyl-1,3-oxazolidin-2-one with
diverse aldehydes in the presence of benzenesulfinic acid.16
Despite these advances, the development of new and direct meth-
odologies for the Lewis acid catalyzed synthesis of oxazolo[3,4-b]tet-
rahydroisoquinolin-3-ones remains largely unrealized. Herein we
Therefore, efficient syntheses of 2-azapodophyllotoxin ana-
logues, oxazolo[3,4-b]tetrahydroisoquinolin-3-ones, are of inter-
est. The well-known Bischler–Napieralski11 or Pictet–Spengler12
reactions are powerful and classic tools for constructing the corre-
sponding N-containing heterocyclic derivatives via the ring closure
of iminium intermediates. Vandewalle et al. reported the Bischler–
Napieralski method to obtain 2-azapodophyllotoxins.13 The C1-
substituted dihydroisoquinoline precursor structure was built first,
after which the reaction afforded the target products through
reduction and condensation, respectively. At almost the same time,
Pictet–Spengler reactions promoted by a Bronsted acid, such as
describe a facile, straightforward, and efficient procedure to
obtain highly diastereoselective 5-substituted oxazolo[3,4-b]tetra-
hydroisoquinolin-3-ones through the Pictet–Spengler reaction of
(S)-4-benzyl-2-oxazolidinone with various aldehydes in the pres-
ence of Lewis acid trimethylsilyl trifluoromethanesulfonate
(TMSOTf).17
2. Results and discussion
We began our study by investigating the condensation reaction
of commercially available (S)-4-benzyl-2-oxazolidinone 1 with
benzaldehyde 2a. Different Lewis acids including ZnCl2, FeCl3,
SnCl5ꢀ5H2O, AlCl3, TiCl4, BF3ꢀEt2O, TMSCl, and TMSOTf were
employed to screen the reaction in dry toluene at room tempera-
ture as shown in Table 1. We found that when the reaction was
⇑
Corresponding authors. Tel.: +86 18240693237 (T.-X.L.).
E-mail addresses: liutongxin_0912@126.com (T.-X. Liu), zgs6668@yahoo.com
(G. Zhang).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.10.015

1592
Z. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 1591–1597
H
OH
H
R
R'
H
N
O
O
O
O
O
O
O
O
MeO
OMe
MeO
OMe
OMe
OMe
podophyllotoxin
R'
O
O
R''
N
R
OMe
CO2H
O
H
Me
O
R'
H
N
O
O
H
NMe
NH
Me
R''
N
Me
OH
H
O
N
O
MeO
OMe
H
O
ligands,
Me
auxiliaries,
and catalysts
quinocarcin
Me
renieramycin G
Figure 1. Oxazolo[3,4-b]tetrahydroisoquinolin-3-one compounds and their application.
Table 1
Optimization of the reaction conditions for the synthesis of oxazolo[3,4-b]tetrahydroisoquinolin-3-one 3a from (S)-4-benzyl-2-oxazolidinone 1 with benzaldehyde 2aa
O
CHO
O
Lewis acid
rt
O
NH
Bn
+
N
O
1
2a
3a
Entry
Lewis acid
Solvent
Time (h)
Yieldb (%)
dec (%)
1
2
3
4
5
6
7
8
9
10
ZnCl2
FeCl3
Toulene
Toulene
Toulene
Toulene
Toulene
Toulene
Toulene
Toulene
CH2Cl2
6, 12
6, 12
6, 12
6, 12
6, 12
6, 12
6, 12
6
Trace, trace
37, 42
27, 51
23, 28
Trace, trace
Trace, 9
46, 49
89d
/
99
98
99
/
SnCl5ꢀ5H2O
AlCl3
TiCl4
TMSCl
BF3ꢀEt2O
TMSOTf
TMSOTf
TMSOTf
/
97
98
79
80
23
19
81
52
CHCl3
a
b
c
Reaction conditions: 1 (0.30 mmol), 2a (0.45 mmol), and Lewis acid (0.36 mmol) in solvent (1.0 mL) under room temperature.
LC–MS yields.
Determined by HPLC analysis.
Isolated yield.
d

Z. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 1591–1597
1593
promoted by FeCl3, SnCl5ꢀ5H2O, or AlCl3, it afforded the desired
Table 2 (continued)
Aldehyde 2
CHO
product in a lower yield along with most of the starting materials
after 6 h, although with high diastereoselectivity (Table 1, entries
2–4), while ZnCl2, TiCl4, and TMSCl were ineffective in promoting
Time (h)
Product 3
CO2Me
Yieldb (%)
dec (%)
O
27
95
97
Table 2
CO2Me
Synthesis of oxazolo[3,4-b]tetrahydroisoquinolin-3-ones 3a–o from (S)-4-benzyl-2-
N
oxazolidinone 1 with various aldehydes 2a–oa
2g
O
R
O
O
3g
NO2
CHO
TMSOTf
N
NH
Bn
O
R
CHO
O
+
toulene, rt
O
22
98
98
1
2a-o
Time (h)
3a-o
NO2
N
N
N
Aldehyde 2
Product 3
Yieldb (%)
dec (%)
2h
O
CHO
3h
CHO
Br
O
6
89
98
N
O
Br
O
2a
22
99
99
2i
O
3a
CHO
3i
CHO
F
O
28
90
>99
F
F
O
N
O
22
97
>99
2b
2j
O
3b
OMe
3j
CHO
CHO
O
O
35
83
>99
F
22
97
>99
OMe
N
N
2k
N
N
N
N
O
2c
O
3k
3l
3c
NMe2
O
CHO
O
(HCHO)n 2l
6
6
94
91
/
19d
22
5
83
99
97
>99
O
(CH2)2CHO
(CH2)2Ph
NMe2
O
2d
O
N
N
>99
O
2m
3d
Br
CHO
3m
C(CH3)3
O
(CH3)3CCHO 2n
72
28
48
91
99
O
O
93
Br
3n
2e
O
CHO
3e
F
CHO
O
99
N
2o
O
O
3o
>99
F
a
Reaction conditions: Compound
1
(0.30 mmol), Aldehyde
TMSOTf (0.36 mmol), Toulene (3.0 mL), Room temperature.
2
(0.45 mmol),
2f
O
b
Isolated yield.
Determined by HPLC analysis.
3f
c
d
The reaction was carried out at ꢁ10 °C.

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Z. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 1591–1597
the reaction (Table 1, entries 1, 5, and 6). These Lewis acids had low
efficiency for this reaction, even if prolonging the reaction time to
12 h (Table 1, entries 1–6). Further screening of the conditions
showed that BF3ꢀEt2O was also less effective in producing oxazol-
o[3,4-b]tetrahydroisoquinolin-3-one 3a (Table 1, entry 7), which
was consistent with the previous report.14 When the reaction
was carried out for 6 h in the presence of TMSOTf under the same
conditions, 3a was obtained with high yield and diastereoselectiv-
ity in an efficient manner (Table 1, entry 8). The trans-structure of
3a as the major diastereomer was confirmed by the NOE effect as
illustrated in a previous example,4 and the absolute configuration
of the newly formed stereogenic center in compound 3a was
unequivocally determined as (R) by X-ray single-crystal analysis,18
which was in agreement with the observations obtained by
Katritzky15 and Marino Petrini.16a Further solvent screening
showed CH2Cl2 and CHCl3 to not be the best choice for the reaction,
because the reaction time needed to be prolonged significantly,
while the diastereoselectivity of product decreased (Table 1,
entries 9 and 10).
Under the optimized conditions, we proceeded to explore the
scope of the TMSOTf-mediated Pictet–Spengler reaction of (S)-4-
benzyl-2-oxazolidinone 1 with various aldehydes. The results are
shown in Table 2. It was found that the reactions proceeded
smoothly to afford the desired products in good yields and with
high diastereoselectivity, when different aldehydes including aro-
matic, aliphatic, and cyclic 2a–o were employed. A wide range of
substituted aromatic aldehydes with electron donating and elec-
tron withdrawing groups 2b–k, even the sterically hindered
ortho-substituted aldehydes 2i and 2j, also reacted efficiently to
give the target products 3 in good to high yields and high selectiv-
ity, which did not show the obvious effects on the yield, except for
the reaction time. According to LC–MS analysis of the reaction mix-
tures for 2c and 2d, a small amount of unknown by-products was
observed in the reaction, which might be due to the lower electro-
philicity arising from the existence of a strong electron-rich substi-
tuent (OMe and NMe2). The reactivity of aliphatic aldehydes, such
as 2l and 2m, was similar to aromatic aldehydes 2a and 2f, and
gave the corresponding annulated products 3l and 3m in 94%
and 91% yields, respectively. However, in the case of pivalaldehyde
2n, because of the large steric hindrance of the tert-butyl group, it
only afforded 3n in moderate yield after 72 h, along with most of
the starting materials. Cyclic aldehyde cyclohexanecarbaldehyde
2o was also compatible, efficiently providing the desired 3o.
In order to establish a rational reaction mechanism, a control
experiment was carried out. Treatment of (S)-4-benzyl-2-oxazolid-
inone 1 and benzaldehyde 2a with 1.2 equiv of TfOH under other-
wise identical conditions gave only 3a in 40% isolated yield (93%
de) with 50% recovery of 1 after 6 h, thus implying that the Bron-
sted acid TfOH generated from TMSOTf in the reaction was not
responsible for the actual catalysis.
compound 3 by an attack of the phenyl ring nucleus on the C@N+
double bond of the N-acyliminium intermediate B. With regard
to the diastereoselectivity in the reaction, we thought it was
favorable for an Re attack of the phenyl ring over the course of
the nucleophilic cyclization, that is B to 3, due to the substrate-in-
duced effect of optically active (S)-4-benzyl-2-oxazolidinone,
which made the final compound 3 adopt a more stable trans-
configuration.20 Accordingly, the newly-formed stereocenter has
an (R)-configuration, thus avoiding unfavorable steric interactions.
In addition, there might be an equilibration of the cis/trans
products under these conditions. However, the CAN bond of 3
could be cleaved to give a benzyl cation intermediate, especially
in the presence of Bronsted acid TfOH generated in the reaction,
thus a cis-product could also transform to a trans-isomer via
epimerization.
3. Conclusion
In conclusion, we have developed a facile and alternative meth-
od for the synthesis of oxazolo[3,4-b]tetrahydroisoquinolin-3-ones
3 via a Pictet–Spengler reaction promoted by Lewis acid TMSOTf.
This condensation between (S)-4-benzyl-2-oxazolidinone and
aldehydes represents a straightforward and efficient procedure
for the construction of this type of products in organic synthesis.
It is also associated with a wide range of substrates, excellent
yields and high diastereoselectivity.
4. Experimental
4.1. General
All reagents were obtained from commercial sources and used
without further purification, unless otherwise noted. All reactions
were monitored by TLC with GF254 silica gel coated plates. Flash
column chromatography was carried out by using 200ꢁ300 mesh
silica gel at increased pressure. 1H NMR and 13C NMR spectra were
recorded on a 400 MHz spectrometer in solutions of CDCl3 using tet-
ramethylsilane as the internal standard, d values are given in ppm
and coupling constants (J) in Hz. The high resolution mass spectra
were measured on a MicroTOF mass spectrometer. Melting points
were measured on a melting point apparatus equipped with a ther-
mometer and are uncorrected. Diastereoisomer ratios were deter-
mined by HPLC analysis with Extend-C18 columns (0.46 ꢂ 15 cm)
with a mixture of water and acetonitrile as mobile phase.
4.2. General procedure for the Pictet–Spengler reaction of (S)-4-
benzyl-2-oxazolidinone with various aldehydes in the presence
of TMSOTf
A
mixture of (S)-4-benzyloxazolidin-2-one
1
(53.1 mg,
0.30 mmol) and aldehyde 2 (0.45 mmol) was first added to a dry
round-bottom flask (25 mL), and then dissolved in dry toluene
(1.0 mL). Next, TMSOTf (65 lL, 0.36 mmol) was added to the mix-
ture dropwise in approximately 1 min, after which the resulting
Based on the above control experiment, a plausible formation
mechanism of compounds 3 was proposed as shown in Scheme 1.
First, intermediate A was generated in the presence of TMSOTf, fol-
lowed by a loss of TMSOH to afford N-acyliminium ion intermedi-
ate B.15,16a,19 Next, the ring closure reaction proceeded to give
solution was stirred vigorously at room temperature (monitored
favor
OTMS
R
R
O
O
O
O
"Re"
R
RCHO
N
-TMSOH
NH
N
N
2
O
O
O
O
TMSOTf
-TfOH
OTf
1
A
B
3
Scheme 1. Proposed reaction mechanism.

Z. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 1591–1597
1595
by TLC). Water (25 mL) was then added to the mixture when the
reaction was completed. The aqueous layer was extracted with
3 ꢂ 15 mL of DCM. The combined organic layer was dried over
anhydrous MgSO4, after which the solvent was removed under
reduced pressure. The residue was purified by column chromatog-
raphy on silica gel using petroleum ether and ethyl acetate (10:1)
as the eluent to afford the desired product 3.
126.7, 112.1, 68.4, 55.8, 47.9, 40.4, 34.3; HRMS (ESI) m/z [M+H]+
calcd for C19H20N2O2 309.1598, found: 309.1598.
4.2.5. (5R,10aS)-5-(4-Bromophenyl)-1,5,10,10a-tetrahydro [1,3]
oxazolo[3,4-b]isoquinolin-3-one 3e
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), 4-bromo-
benzaldehyde (0.45 mmol, 83.3 mg), and TMSOTf (0.36 mmol,
65 lL) were used according to the general procedure. The reaction
4.2.1. (5R,10aS)-5-Phenyl-1,5,10,10a-tetrahydro[1,3]oxazolo [3,
4-b]isoquinolin-3-one 3a15
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), benzalde-
hyde (0.45 mmol, 46 lL), and TMSOTf (0.36 mmol, 65 lL) were
was completed in 22 h (102.9 mg, 99%); Rf = 0.41 (Petroleum ether/
EtOAc 2:1); ½a 2D3
¼ ꢁ178 (c 0.28, CHCl3); White solid; mp: 170–
ꢃ
172 °C; 93% de; 1H NMR (400 MHz, CDCl3) d 7.43 (d, J = 8.0 Hz,
2H), 7.33–7.17 (m, 4H), 7.13 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 7.6 Hz,
1H), 5.99 (s, 1H), 4.47 (t, J = 8.4 Hz, 1H), 4.13 (dd, J = 4.4, 8.8 Hz,
1H), 4.04 (dq, J = 4.4, 8.4 Hz, 1H), 3.05 (dd, J = 4.4, 15.6 Hz, 1H),
2.96 (dd, J = 10.8, 15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
156.6, 141.1, 133.4, 132.4, 131.8, 130.4, 129.4, 128.7, 127.6,
127.1, 122.2, 68.6, 55.7, 48.1, 34.3; HRMS (ESI) m/z [M+H]+ calcd
for C17H14BrNO2 344.0281, found: 344.0268.
used according to the general procedure. The reaction was com-
pleted in 6 h (71.0 mg, 89%); Rf = 0.38 (Petroleum ether/EtOAc
2:1); ½a 2D3
¼ ꢁ261 (c 0.68, CHCl3); White solid; mp: 157–159 °C;
ꢃ
98% de; 1H NMR (400 MHz, CDCl3) d 7.32–7.15 (m, 8H), 6.98 (d,
J = 7.6 Hz, 1H), 6.04 (s, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.13–4.04 (m,
2H), 3.04 (dd, J = 4.4, 15.6 Hz, 1H), 2.96 (dd, J = 10.6, 15.6 Hz, 1H);
HRMS (ESI) m/z calcd for C17H15NO2 [M+H]+ 266.1176, found:
266.1172.
4.2.6. (5R,10aS)-5-(4-Fluorophenyl)-1,5,10,10a-tetrahydro [1,3]
oxazolo[3,4-b]isoquinolin-3-one 3f
4.2.2. (5R,10aS)-5-(p-Tolyl)-1,5,10,10a-tetrahydro[1,3]oxazolo [3,
4-b]isoquinolin-3-one 3b
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), p-tolualde-
hyde (0.45 mmol, 53.0 lL), and TMSOTf (0.36 mmol, 65 lL) were
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), 4-fluoro-
benzaldehyde (0.45 mmol, 47.4
lL), and TMSOTf (0.36 mmol,
65 L) were used according to the general procedure. The reaction
l
was completed in 5 h (82.4 mg, 97%); Rf = 0.34 (Petroleum ether/
used according to the general procedure. The reaction was com-
EtOAc 2:1); ½a 2D3
¼ ꢁ219 (c 0.15, CHCl3); Yellow solid; mp: 135–
ꢃ
pleted in 28 h (75.2 mg, 90%); Rf = 0.33 (Petroleum ether/EtOAc
138 °C; >99% de; 1H NMR (400 MHz, CDCl3) d 7.29–7.19 (m, 5H),
7.03–6.97 (m, 3H), 6.04 (s, 1H), 4.49 (t, J = 8.4 Hz, 1H), 4.15 (dd,
J = 4.4, 8.4 Hz, 1H), 4.07 (dq, J = 4.4, 8.4 Hz, 1H), 3.07 (dd, J = 4.4,
15.6 Hz, 1H), 2.98 (dd, J = 10.8, 15.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 163.4 (d, J = 245.4 Hz), 156.6, 138.1 (d, J = 3.0 Hz), 133.8,
132.4, 130.4 (d, J = 8.2 Hz), 129.4, 128.7, 127.6, 127.0, 115.5 (d,
J = 21.3 Hz), 68.6, 55.6, 48.0, 34.4; HRMS (ESI) m/z [M+H]+ calcd
for C17H14FNO2 284.1081, found: 284.1076.
2:1); ½a 2D3
¼ ꢁ238 (c 0.08, CHCl3); White solid; mp: 150–152 °C;
ꢃ
>99% de; 1H NMR (400 MHz, CDCl3) d 7.28–7.13 (m, 7H), 7.02 (d,
J = 7.6 Hz, 1H), 6.04 (s, 1H), 4.47 (t, J = 8.0 Hz, 1H), 4.16–4.07 (m,
2H), 3.07 (dd, J = 4.4, 15.6 Hz, 1H), 2.99 (dd, J = 10.4, 15.6 Hz, 1H),
2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) d 156.6, 139.3, 137.8,
134.2, 132.4, 129.31, 129.26, 128.8, 128.6, 127.3, 126.9, 68.5,
56.1, 48.1, 34.4, 21.1; HRMS (ESI) m/z [M+H]+ calcd for
C18H17NO2 280.1332, found: 280.1332.
4.2.3. (5R,10aS)-5-(4-Methoxyphenyl)-1,5,10,10a-tetrahydro [1,3]
oxazolo[3,4-b]isoquinolin-3-one 3c
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), p-methoxy-
benzaldehyde (0.45 mmol, 55.3 lL), and TMSOTf (0.36 mmol, 65 lL)
4.2.7. Methyl 4-((5R,10aS)-3-Oxo-1,5,10,10a-tetrahydro[1,3]
oxazolo[3,4-b]isoquinolin-5-yl)benzoate 3g
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), methyl p-
formylbenzoate (0.45 mmol, 73.8 mg), and TMSOTf (0.36 mmol,
were used according to the general procedure. The reaction was
65 lL) were used according to the general procedure. The reaction
was completed in 27 h (92.1 mg, 95%); ½a D23
¼ ꢁ230 (c 0.25, CHCl3);
ꢃ
completed in 35 h (73.5 mg, 83%); Rf = 0.26 (Petroleum ether/EtOAc
2:1); ½a 2D3
¼ ꢁ214 (c 0.10, CHCl3); White solid; mp: 124–125 °C;
ꢃ
Rf = 0.21 (Petroleum ether/EtOAc 2:1); White solid; mp: 184–
185 °C; 97% de; 1H NMR (400 MHz, CDCl3) d 7.99 (d, J = 7.6 Hz,
2H), 7.34 (d, J = 8.0 Hz, 2H), 7.27–7.17 (m, 3H), 6.95 (d, J = 7.6 Hz,
1H), 6.07 (s, 1H), 4.49 (t, J = 8.4 Hz, 1H), 4.17–4.06 (m, 2H), 3.90
(s, 3H), 3.10–2.94 (m, 2H); 13C NMR (100 MHz, CDCl3) d 230.1,
166.7, 156.7, 146.9, 133.2, 132.4, 130.0, 129.8, 129.5, 128.7,
127.7, 127.1, 68.6, 56.0, 52.2, 48.3, 34.3; HRMS (ESI) m/z [M+H]+
calcd for C19H17NO4 324.1230, found: 324.1228.
>99% de; 1H NMR (400 MHz, CDCl3) d 7.19–7.08 (m, 5H), 6.93 (d,
J = 7.6 Hz, 1H), 6.76 (d, J = 8.4 Hz, 2H), 5.94 (s, 1H), 4.40 (t,
J = 8.4 Hz, 1H), 4.05 (dd, J = 8.4, 4.4 Hz, 1H), 4.02–3.96 (m, 2H),
3.71 (s, 3H), 2.97 (dd, J = 4.4, 15.6 Hz, 1H), 2.89 (dd, J = 10.4,
15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 159.3, 134.5, 134.3,
132.3, 129.9, 129.2, 128.8, 127.3, 126.9, 113.9, 68.5, 55.7, 55.3,
48.0, 34.4; HRMS (ESI) m/z [M+H]+ calcd for C18H17NO3 296.1281,
found: 296.1278.
4.2.8. (5R,10aS)-5-(4-Nitrophenyl)-1,5,10,10a-tetrahydro[1,3]
oxazolo[3,4-b]isoquinolin-3-one 3h15
4.2.4. (5R,10aS)-5-(4-(Dimethylamino)phenyl)-1,5,10,10a-tetra-
hydro[1,3]oxazolo[3,4-b]isoquinolin-3-one 3d
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), p-nitro-
benzaldehyde (0.45 mmol, 68 mg), and TMSOTf (0.36 mmol,
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), p-dimeth-
ylaminobenzaldehyde (0.45 mmol, 67.1 mg), and TMSOTf
65 lL) were used according to the general procedure. The reaction
(0.36 mmol, 65 lL) were used according to the general procedure.
was completed in 22 h (91.2 mg, 98%); Rf = 0.23 (Petroleum ether/
The reaction was carried out at ꢁ10 °C. The reaction was com-
EtOAc 2:1); ½a 2D3
¼ ꢁ240 (c 0.25, CHCl3); Yellow solid; mp: 153–
ꢃ
pleted in 19 h (77.5 mg, 83%); Rf = 0.26 (Petroleum ether/EtOAc
156 °C; 98% de; 1H NMR (400 MHz, CDCl3) d 8.06 (d, J = 8.4 Hz,
2H), 7.37 (d, J = 8.4 Hz, 2H), 7.22–7.11 (m, 3H), 6.84 (d, J = 7.6 Hz,
1H), 6.01 (s, 1H), 4.44 (t, J = 8.4 Hz, 1H), 4.10 (dd, J = 4.4, 8.4 Hz,
1H), 4.04–3.97 (m, 1H), 3.02 (dd, J = 4.0, 15.6 Hz, 1H), 2.90 (dd,
J = 11.2, 15.6 Hz, 1H); HRMS (ESI) m/z [M+H]+ calcd for
2:1); ½a 2D3
¼ ꢁ263 (c 0.56, CHCl3); Yellow solid; mp: 163–164 °C;
ꢃ
>99% de; 1H NMR (400 MHz, CDCl3) d 7.28–7.17 (m, 3H), 7.14 (d,
J = 8.8 Hz, 2H), 7.05 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 8.0 Hz, 2H),
6.02 (s, 1H), 4.47 (t, J = 8.0 Hz, 1H), 4.14–4.07 (m, 2H), 3.06 (dd,
J = 4.4, 15.6 Hz, 1H), 3.01–2.95 (m, 7H); 13C NMR (100 MHz, CDCl3)
d 156.5, 150.1, 134.7, 132.3, 129.9, 129.5, 129.1, 128.8, 127.1,
C17H14N2O4 311.1026, found: 311.1025.

1596
Z. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 1591–1597
4.2.9. (5R,10aS)-5-(2-Bromophenyl)-1,5,10,10a-tetrahydro[1,3]
oxazolo[3,4-b]isoquinolin-3-one 3i
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), 2-bromo-
benzaldehyde (0.45 mmol, 83 mg), and TMSOTf (0.36 mmol,
were used according to the general procedure. The reaction was
completed in 6 h (80.0 mg, 91%); Rf = 0.37 (Petroleum ether/EtOAc
2:1); ½a 2D3
ꢃ
¼ ꢁ200 (c 0.65, CHCl3); Oil; >99% de; 1H NMR (400 MHz,
CDCl3) d 7.30–7.12 (m, 8H), 7.08 (d, J = 7.2 Hz, 1H), 4.98 (dd, J = 3.2,
10.0 Hz, 1H), 4.32 (t, J = 8.4 Hz, 1H), 4.08 (dd, J = 2.8, 8.4 Hz, 1H),
3.93 (dq, J = 2.4, 7.6 Hz, 1H), 2.89–2.72 (m, 4H), 2.30–2.21 (m,
1H), 2.13–2.02 (m, 1H); HRMS (ESI) m/z [M+H]+ calcd for
65 lL) were used according to the general procedure. The reaction
was completed in 22 h (101.8 mg, 99%); Rf = 0.29 (Petroleum ether/
EtOAc 2:1); ½a 2D3
¼ ꢁ223 (c 0.66, CHCl3); Yellow solid; mp: 147–
ꢃ
149 °C; 99% de; 1H NMR (400 MHz, CDCl3) d 7.64 (d, J = 7.6 Hz,
1H), 7.28–7.14 (m, 5H), 7.03 (dd, J = 1.2, 7.6 Hz, 1H), 6.91 (d,
J = 7.6 Hz, 1H), 6.42 (s, 1H), 4.49 (t, J = 8.0 Hz, 1H), 4.26–4.15 (m,
2H), 3.07–2.96 (m, 2H); 13C NMR (100 MHz, CDCl3) d 157.0,
141.7, 134.3, 133.5, 132.3, 130.7, 129.4, 129.3, 128.0, 127.8,
127.5, 127.2, 124.2, 68.3, 56.4, 49.7, 34.0; HRMS (ESI) m/z [M+H]+
calcd for C17H14BrNO2 344.0281, found: 344.0273.
C19H19NO2 294.1489, found: 294.1489.
4.2.14. (5R,10aS)-5-(tert-Butyl)-1,5,10,10a-tetrahydro[1,3]oxaz-
olo[3,4-b]isoquinolin-3-one 3n
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), pivalde-
hyde (0.45 mmol, 48.8 lL), and TMSOTf (0.36 mmol, 65 lL) were
used according to the general procedure. The reaction was com-
pleted in 72 h (36.2 mg, 48%); Rf = 0.46 (Petroleum ether/EtOAc
4.2.10. (5R,10aS)-5-(2-Fluorophenyl)-1,5,10,10a-tetrahydro[1,3]
oxazolo[3,4-b]isoquinolin-3-one 3j
2:1); ½a 2D3
¼ ꢁ70 (c 0.30, CHCl3); White solid; mp: 174–176 °C;
ꢃ
99% de; 1H NMR (400 MHz, CDCl3) d 7.28–7.16 (m, 3H), 7.13 (d,
J = 7.2 Hz, 1H), 4.67 (s, 1H), 4.59 (t, J = 8.0 Hz, 1H), 4.54–4.46 (m,
1H), 4.02 (dd, J = 5.2, 8.4 Hz, 1H), 3.15 (dd, J = 6.8, 16.8 Hz, 1H),
2.84 (dd, J = 8.0, 16.8 Hz, 1H), 1.07 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 157.8, 134.3, 131.9, 129.3, 128.7, 127.3, 125.7, 69.3,
61.3, 49.4, 38.0, 32.7, 28.3; HRMS (ESI) m/z [M+H]+ calcd for
C15H19NO2 246.1489, found: 246.1487.
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), 2-fluoro-
benzaldehyde (0.45 mmol, 47.4
lL), and TMSOTf (0.36 mmol,
65 L) were used according to the general procedure. The reaction
l
was completed in 22 h (82.4 mg, 97%); Rf = 0.32 (Petroleum ether/
EtOAc 2:1); ½a 2D3
¼ ꢁ268 (c 0.30, CHCl3); White solid; mp: 153–
ꢃ
155 °C; >99% de; 1H NMR (400 MHz, CDCl3) d 7.33–7.02 (m, 7H),
6.91 (d, J = 7.6 Hz, 1H), 6.12 (s, 1H), 4.50 (t, J = 8.4 Hz, 1H), 4.24
(dq, J = 4.0, 8.0 Hz, 1H), 4.17 (dd, J = 3.6, 8.4 Hz, 1H), 3.04 (dd,
J = 4.4, 15.6 Hz, 1H), 2.97 (dd, J = 10.8, 15.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 160.7 (d, J = 246.9 Hz), 157.0, 134.1, 132.1,
131.2 (d, J = 4.1 Hz), 130.0 (d, J = 8.1 Hz), 129.3, 129.2 (d,
J = 13.9 Hz), 127.6, 127.3, 127.1, 124.2 (d, J = 3.4 Hz), 116.2 (d,
J = 21.5 Hz), 68.4, 52.7, 49.3 (d, J = 3.3 Hz), 34.5; HRMS (ESI) m/z
[M+H]+ calcd for C17H14FNO2 284.1081, found: 284.1081.
4.2.15. (5R,10aS)-5-Cyclohexyl-1,5,10,10a-tetrahydro[1,3]oxaz-
olo[3,4-b]isoquinolin-3-one 3o15
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), cyclohex-
anecarboxaldehyde (0.45 mmol, 54.4
lL), and TMSOTf (0.36 mmol,
65 L) were used according to the general procedure. The reaction
l
was completed in 28 h (73.6 mg, 91%); Rf = 0.44 (Petroleum ether/
EtOAc 2:1); ½a 2D3
¼ ꢁ151 (c 0.24, CHCl3); White solid; mp: 139–
ꢃ
141 °C; 99% de; 1H NMR (400 MHz, CDCl3) d 7.28–7.17 (m, 3H),
7.11 (d, J = 7.6 Hz, 1H), 4.79 (d, J = 4.0 Hz, 1H), 4.57 (t, J = 8.0 Hz,
1H), 4.79 (d, J = 4.0 Hz, 1H), 4.12–4.05 (m, 1H), 2.91 (dd, J = 5.2,
15.6 Hz, 1H), 2.85 (dd, J = 10.0, 15.6 Hz, 1H), 2.00–1.64 (m, 5H),
1.46–0.95 (m, 6H); HRMS (ESI), m/z [M+H]+ calcd for C17H21NO2
272.1645, found: 272.1644.
4.2.11. (5R,10aS)-5-(3-Fluorophenyl)-1,5,10,10a-tetrahydro[1,3]
oxazolo[3,4-b]isoquinolin-3-one 3k
(S)-4-Benzyloxazolidin-2-one (53.1 mg, 0.30 mmol), m-fluoro-
benzaldehyde (0.45 mmol, 47.5
lL), and TMSOTf (0.36 mmol,
65 L) were used according to the general procedure. The reaction
l
was completed in 22 h (81.5 mg, 96%); Rf = 0.35 (Petroleum ether/
EtOAc 2:1); ½a 2D3
ꢃ
¼ ꢁ250 (c 0.37, CHCl3); White solid; mp: 160–
Acknowledgments
163 °C; >99% de; 1H NMR (400 MHz, CDCl3) d 7.33–7.19 (m, 4H),
7.11 (d, J = 7.6 Hz, 1H), 7.03–6.97 (m, 2H), 6.90 (d, J = 2.0, 9.6 Hz
1H), 6.04 (s, 1H), 4.50 (t, J = 8.4 Hz, 1H), 4.15 (dd, J = 4.4, 8.8 Hz,
1H), 4.07 (dq, J = 4.4, 8.4 Hz, 1H), 3.06 (dd, J = 4.4, 15.6 Hz, 1H),
2.98 (dd, J = 10.8, 15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 162.8
(d, J = 245.6 Hz,), 156.6, 144.4 (d, J = 6.4 Hz), 133.3, 132.4, 130.2 (d,
J = 8.1 Hz), 129.4, 128.7, 127.7, 127.1, 124.5 (d, J = 2.7 Hz), 115.5
(d, J = 21.8 Hz), 115.0 (d, J = 21.1 Hz), 68.6, 55.8, 48.2, 34.3; HRMS
(ESI) m/z [M+H]+ calcd for C17H14FNO2 284.1081, found: 284.1083.
We thank the NSFC (21002051, 21172056 and 21272057),
PCSIRT (IRT1061), China Postdoctoral Science Foundation funded
project (2012M521397, 2013T60701 and 2013M530339), the Nat-
ural Science Foundation of Henan Province (122300410296) and
Key Project of Henan Educational Committee (13A150546) for
financial support of this research.
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65 lL) were used according to the general procedure. The reaction
was completed in 6 h (53.3 mg, 94%); Rf = 0.16 (Petroleum ether/
EtOAc 2:1); ½a 2D3
¼ ꢁ18 (c 0.04, CHCl3); White solid; mp: 135–
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