An efficient synthesis of 2-(trifluoromethyl)-2H-[1,3]oxazino[2,3-a] isoquinolines via a three-component cascade approach using a continuous-flow microreactor

Article abstract of DOI:10.1055/s-0031-1290809

The three-component reaction between an isoquinoline, a dialkyl acetylenedicarboxylate and 2,2,2-trifluoro-1-phenylethanone involving a 1,4-dipolar cycloaddition cascade approach is developed using a continuous-flow microreactor. The reaction conditions (solvent, flow rate and temperature) are optimized leading to the synthesis 2-(trifluoromethyl)-2H-[1,3]oxazino[2,3-a] isoquinoline derivatives in 79-83% isolated yields, whilst eliminating the formation of 11bH-pyrido[2,1-a]isoquinoline-1,2,3,4-tetracarboxylate by-products. The continuous-flow method is also applied to similar reactions using aromatic aldehydes as the carbonyl component. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290809

SPECIAL TOPIC
▌2519
sApencialEtopfifcicient Synthesis of 2-(Trifluoromethyl)-2H-[1,3]oxazino[2,3-a]isoquino-
lines via a Three-Component Cascade Approach Using a Continuous-Flow
Microreactor
Multicomponent Reactions in a Microreactor
Ming Lei,*a,b Wan Tian,a Ruijun Hu,a Wei Li,a Hong Zhang*b,c
a
Department of Chemistry, Zhejiang University, 310027 Hangzhou, P. R. of China
Fax +86(571)87951895; E-mail: leiming@zju.edu.cn
b
Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Zhejiang University Medical PET Center, 310009 Hangzhou, P. R. of
China
Fax +86(571)87767188; E-mail: hzhang21@gmail.com
c
Department of Nuclear Medicine, Second Affiliated Hospital of Zhejiang University, School of Medicine, 310009 Hangzhou, P. R. of China
Received: 18.02.2012; Accepted: 05.03.2012
methods. By conducting multicomponent reactions in a
Abstract: The three-component reaction between an isoquinoline,
microreactor, the advantages of both techniques can be
a dialkyl acetylenedicarboxylate and 2,2,2-trifluoro-1-phenyleth-
combined such that reaction screening and optimization
of the conditions would become more convenient. The
anone involving a 1,4-dipolar cycloaddition cascade approach is de-
veloped using a continuous-flow microreactor. The reaction
conditions (solvent, flow rate and temperature) are optimized lead- process would be facilitated by continuous-flow condi-
ing to the synthesis 2-(trifluoromethyl)-2H-[1,3]oxazino[2,3-a]iso-
quinoline derivatives in 79-83% isolated yields, whilst eliminating
the formation of 11bH-pyrido[2,1-a]isoquinoline-1,2,3,4-tetracar-
tions and a large number of reactions could be conducted
rapidly in a sequential manner.
The 1,4-dipolar cycloaddition established by Huisgen is a
very important method to construct six-membered hetero-
cycles via the reaction of a 1,4-dipolar intermediate,
generated from an isoquinoline and an acetylenedicarbox-
ylate, with a dipolarophile such as phenyl isocyanate,
diethyl mesoxalate, or dimethyl azodicarboxylate.4 Fol-
lowing Huisgen’s pioneering contributions, cycloaddi-
tions of 1,4-dipolar intermediates with N-tosylimines and
other dipolarophiles have also been explored in the last
decade.5 However, in a batch reactor, a side reaction be-
tween the 1,4-dipolar intermediate and the acetylenedicar-
boxylate can occur to generate the cycloaddition by-
product, 11bH-pyrido[2,1-a]isoquinoline-1,2,3,4-tetra-
carboxylate, along with suppression of the desired cyclo-
addition reaction.4,6 We envisioned that in a flow
microreactor this side reaction would be minimized if the
1,4-dipolar intermediate were trapped in situ by the dipo-
larophile, by virtue of the excellent mixing of reagents.
Our previous work demonstrated the efficient acylation of
ferrocene with various acid anhydrides using a microflu-
idic chip reactor; the yields and selectivities were im-
proved compared to classical batch systems.3m As part of
our continued research to develop new synthetic methods
based on multicomponent reactions in a microreactor, we
herein demonstrate the advantages of using a flow process
to facilitate the three-component 1,4-dipolar cycloaddi-
tion between an isoquinoline, a dialkyl acetylenedicar-
boxylate and 2,2,2-trifluoro-1-phenylethanone (3a), in
high efficiency and selectivity compared with a typical
batch system. The introduction of the electron-withdraw-
ing trifluoromethyl group activates the ketones as dipola-
rophiles in the 1,4-dipolar cycloaddition reaction.
Moreover, compounds containing a trifluoromethyl group
have shown applications in medicinal chemistry.7,8
boxylate by-products. The continuous-flow method is also applied
to similar reactions using aromatic aldehydes as the carbonyl com-
ponent.
Key words: multicomponent reactions, microreactor, 1,4-dipolar
cycloaddition, continuous-flow system, 2-(trifluoromethyl)-2H-
[1,3]oxazino[2,3-a]isoquinolines
Multicomponent reactions are generally defined as a class
of reactions involving at least three different substrates to
form products via a cascade process. This strategy allows
the formation of multiple bonds and the assembly of com-
plicated skeletons in a one-pot manner, without the isola-
tion of intermediates, and thereby greatly enhances the
synthetic efficiency. As multicomponent reactions com-
bine two major principles of organic synthesis – conver-
gence and atom-economy – they have found widespread
applications in organic, combinatorial and medicinal
chemistry.1
Microreactors have attracted significant interest and have
been employed to carry out a large number of different re-
actions.2,3 In comparison with the classical batch systems,
microreactors require less space, energy and reagents, and
can afford improved yields of products in shorter reaction
times. In addition, they produce less waste because of the
short diffusion distances, large specific surface areas, ef-
ficient mixing and increased thermal transfer. The use of
microreactors also enables the precise control of reactive
intermediates and thereby facilitates highly selective reac-
tions which can be difficult to achieve using conventional
SYNTHESIS 2012, 44, 2519–2526
Advanced online publication: 08.05.2012
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DOI: 10.1055/s-0031-1290809; Art ID: SS-2012-C0167-ST
© Georg Thieme Verlag Stuttgart · New York

2520
M. Lei et al.
SPECIAL TOPIC
COOEt
N
COOEt
COOEt
O
MeCN
20 °C, 10 h
N
COOEt
COOEt
O
+
+
+
CF3
N
CF3
EtOOC
COOEt
1a
2a
3a
COOEt
4a, 54%
5, 20%
Scheme 1 Three-component 1,4-dipolar cycloaddition reaction in a batch flask system
In order to transfer the cycloaddition reaction to a contin- formed at 20 °C. Yields of 86–88% of 4a (determined by
uous-flow microreactor, preliminary solvent screening HPLC) were obtained which were significantly higher
was conducted in a batch flask system using the model re- than that achieved from the batch process at the same tem-
action between isoquinoline (1a), diethyl acetylenedicar- perature. Moreover, the by-product 5 was not present ac-
boxylate (2a) and 2,2,2-trifluoro-1-phenylethanone (3a) cording to liquid chromatography–mass spectrometry
in a 1:1.1:1.1 molar ratio. At 20 °C, the progress of the cy- (LC–MS). The dramatic effect of the microflow system
cloadditions in dichloromethane, tetrahydrofuran, 1,4-di- would appear to be attributable to the extremely rapid and
oxane, ethanol, acetonitrile and toluene were evaluated by efficient mixing of reagents by virtue of the short diffu-
thin-layer chromatography (TLC). A comparatively high sion path in the micromixer. Encouraged by these results,
isolated yield (54%) of 2-(trifluoromethyl)-2H-[1,3]oxa- we next examined the reaction at 30 °C which resulted in
zino[2,3-a]isoquinoline 4a was obtained in acetonitrile slightly increased yields of 4a (88–90%). When the tem-
which was accompanied with the expected by-product, perature was raised to 50 °C, the reaction afforded 86%,
tetraethyl 11bH-pyrido[2,1-a]isoquinoline-1,2,3,4-tetra- 95%, 92% and 93% yields corresponding to the above
carboxylate (5) in 20% yield.
flow rates, respectively, whilst heating at 60 °C led to
91%, 92%, 85% and 85% yields. In general, the reaction
at a flow rate of 4 μL/min afforded the highest yields of
product 4a. The best yield of 95% (according to HPLC
analysis) was obtained at 50 °C with a residence time of
60 minutes.
We next investigated adapting the model reaction into a
continuous-flow process using acetonitrile as the solvent.
The continuous-flow system was constructed using a
Harvard PHD 2000 syringe pump, 1001-RN gas-tight sy-
ringes, a water bath, a Y-shaped mixer and stainless steel
tubing and fittings (Figure 1). Solution A [isoquinoline For comparative purposes the model reaction was also
(1a) in acetonitrile (0.1 M)] and solution B [an equimolar carried out in a batch flask at 50 °C, in a one-pot manner
mixture of 2a and trifluoro-phenylethanone 3a in acetoni- over two hours. The yield of product 4a was 41% and that
trile (0.11 M)] were introduced into the mixer unit at iden- of by-product 5 increased to 34% (Scheme 2). This result
tical flow rates using the syringe pump. The mixture was indicated that at higher temperatures the rate of the side
then allowed to flow through a stainless steel tube reactor reaction increased, whilst the extent of the desired cyclo-
(Ø = 500 μm, l = 1.5 m) which was submerged in a water addition was reduced. In the microreactor, the flow pro-
bath. The outlet solution was collected and the yields were cess enables continuous generation and in situ
quantified using high-performance liquid chromatogra- consumption of the intermediate formed between isoquin-
phy (HPLC).
oline (1a) and diethyl acetylenedicarboxylate (2a). This
fact, combined with the excellent mixing associated with
the flow technique, completely eliminated formation of
the corresponding by-product 5 and ensured that this cas-
The model reaction was investigated using the continu-
ous-flow system by varying the flow rate (2, 4, 6 or 8
μL/min) and the temperature. Preliminary testing was per-
Figure 1 Schematic of the continuous-flow system
Synthesis 2012, 44, 2519–2526
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Multicomponent Reactions in a Microreactor
2521
COOEt
N
COOEt
COOEt
O
MeCN
50 °C, 2 h
N
COOEt
COOEt
O
+
+
+
CF3
N
CF3
EtOOC
COOEt
1a
2a
3a
COOEt
4a, 41%
5, 34%
Scheme 2 A comparative one-pot model reaction in a batch flask system
cade transformation proceeded at a much faster rate com- 2a and 2b, the presence of substituents on the isoquinoline
pared to the batch system.
and trifluoro-phenylethanone substrates resulted in high
yields of isolated cycloaddition products (Table 1, entries
1–12). In the case of methyl propiolate (2c), the loss of
one of the electron-withdrawing carboxylate groups led to
decreased activity and resulted in a low 30% yield of the
cycloaddition product 4m (Table 1, entry 13). In addition,
other carbonyl compounds were investigated as dipolaro-
In order to investigate the scope and limitations of this
three-component cascade reaction exploiting the micro-
reactor, a series of 2-(trifluoromethyl)-2H-[1,3]oxazi-
no[2,3-a]isoquinolines 4a–m was prepared using the
optimized conditions. The results are summarized in Ta-
ble 1. With highly active dialkyl acetylenedicarboxylates
Table 1 Three-Component 1,4-Dipolar Cycloaddition in a Flow Microreactor
R1
R1
50 °C
4 µL/min
N
N
R2
R3
1
in MeCN
O
R2
R4
O
+
R4
R3
R5
R5
2
3
4
Entry
Isoquinoline (R1)
Alkyne (R2/R3)
Carbonyl compound (R4/R5)
Product
Yield (%)a
1
2
1a (H)
1a
2a (CO2Et/CO2Et)
3a (CF3/H)
3b (CF3/Br)
3c (CF3/F)
3a (CF3/H)
3b (CF3/Br)
3c (CF3/F)
3a (CF3/H)
3b (CF3/Br)
3c (CF3/F)
3a (CF3/H)
3b (CF3/Br)
3c (CF3/F)
3a (CF3/H)
3d (CH3/H)
3e (H/H)
4a
4b
4c
4d
4e
4f
79
81
82
81
82
83
78
82
83
81
83
83
30
–
2a
2a
3
1a
4
1a
2b (CO2Me/CO2Me)
5
1a
2b
6
1a
2b
7
1b (Me)
1b
2a
4g
4h
4i
8
2a
9
1b
2a
10
11
12
13
14
15
16
17
1b
2b
4j
1b
2b
4k
4l
1b
2b
1a
2c (H/CO2Me)
4m
4n
4o
4p
4q
1a
2a
2a
2a
2a
1a
18
21
91
1a
3f (H/Br)
1a
3g (H/NO2)
a Yield of isolated product based on isoquinoline 1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2519–2526

2522
M. Lei et al.
SPECIAL TOPIC
A
B
R2
R1
R1
R1
+
R1
R2
R3
N
O
R2
R3
N
N
R3
2
N
R2
R3
1
O
[4+2]
R4
R4
R5
R5
3
4
Scheme 3 Proposed mechanism
Three-Component Cycloaddition in a Batch Flask; Typical
Procedure
To a soln of 2,2,2-trifluoro-1-phenylethanone (3a) (87 mg, 0.5
mmol) and diethyl acetylenedicarboxylate (2a) (85 mg, 0.5 mmol)
in MeCN (2 mL) was added isoquinoline (1a) (64.5 mg, 0.5 mmol).
philes under the optimized conditions, the electronic ef-
fects of which were quite apparent. For inactive
acetophenone (3d), no trace of the desired product was de-
tected (Table 1, entry 14). Benzaldehydes gave slightly
better results (Table 1, entries 15 and 16), however, when The mixture was stirred at r.t. for 10 h and then evaporated under
vacuum. The residue was subjected to silica gel column chromatog-
raphy (eluent: PE–EtOAc, 1:4) to give the product 4a (127.7 mg,
54%) and by-product 5 (46.9 mg, 20%).
the benzaldehyde was activated with a strong electron-
withdrawing nitro group, an excellent 91% yield of the
corresponding cycloadduct 4q was obtained (Table 1, en-
try 17).
Tetraethyl 11bH-Pyrido[2,1-a]isoquinoline-1,2,3,4-tetracar-
boxylate (5)
Mechanistically, the first step of the reaction is formation
of 1,4-dipolar intermediate B through nucleophilic attack
of the isoquinoline 1 on the acetylenedicarboxylate 2.
Next, intermediate B is trapped by the carbonyl com-
pound 3 to generate the [4+2] cycloaddition product 4
(Scheme 3).
Yield: 46.9 mg (20%); yellow oil.
IR (KBr): 2984, 1736, 1612, 1514, 1461, 1372, 1232, 1191, 1133,
1028, 909, 774 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.27–7.25 (m, 2 H), 7.13–7.11 (m,
1 H), 7.04–7.02 (m, 1 H), 6.48–6.44 (m, 2 H), 5.76 (s, 1 H), 4.39–
4.31 (m, 4 H), 4.19–4.11 (m, 4 H), 1.41–1.38 (t, J = 7.0 Hz, 3 H),
1.34–1.31 (t, J = 7.5 Hz, 3 H), 1.23–1.20 (t, J = 7.5 Hz, 3 H), 1.16–
1.13 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 167.0, 164.2, 163.4, 162.4, 147.7,
139.2, 128.1, 126.1, 124.0, 123.9, 119.5, 111.4, 97.0, 62.7, 61.5,
61.1, 60.9, 57.2, 14.1, 13.9, 13.8.
In conclusion, we have developed a three-component 1,4-
dipolar cycloaddition reaction of isoquinolines 1, acetyl-
enedicarboxylates 2 and 2,2,2-trifluoro-1-phenylethanone
(3a) in a continuous-flow microreactor. Under the opti-
mized conditions, a series of 2-(trifluoromethyl)-2H-
[1,3]oxazino[2,3-a]isoquinoline derivatives was synthe-
sized in 78–83% isolated yields. The process was also ap-
plied to similar reactions using aromatic aldehydes as the
carbonyl components. In contrast to the corresponding
batch operation, it was found that the microfluidic process
enabled continuous generation and in situ consumption of
1,4-dipolar intermediate B. The excellent mixing of re-
agents associated with the flow technique eliminated the
formation of the by-product 5 and ensured that the cas-
cade transformation proceeded with very high selectivity
and efficiency.
HRMS (ESI): m/z [M]+ calcd for C25H27NO8: 469.1737; found:
469.1743.
Three-Component Cycloaddition in a Flow Microreactor; Gen-
eral Procedure
Soln A (1 mL) [isoquinoline 1 (0.1 M in MeCN)] and soln B (1 mL)
[alkyne 2 (0.11 M in MeCN) and carbonyl compound 3 (0.11 M in
MeCN) ] were transferred into separate gas-tight syringes. The sy-
ringes were placed in a Harvard PHD 2000 syringe pump which was
set to deliver the reactants at a flow rate of 4 μL/min. The heating
bath was set at 50 °C and the process initiated. The output mixture
was collected and then concentrated under vacuum. The residue
was subjected to silica gel column chromatography (eluent: PE–
EtOAc, 1:4) to give the product.
Diethyl 2-Phenyl-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazi-
no[2,3-a]isoquinoline-3,4-dicarboxylate (4a)
Yield: 37.4 mg (79%); yellow oil.
All chemicals (reagent grade) were used as purchased and without
further purification unless otherwise stated. TLC was performed on
Huang Hai HSGF254 silica gel plates. Column chromatography
was performed using Yi Long silica gel 60 (300–400 mesh) silica
gel (300–400 mesh). Petroleum ether (PE) refers to the fraction
boiling in the 60–90 °C range. Melting points were obtained using
a YANACO micro melting point apparatus and are uncorrected. In-
frared spectra were recorded on a Perkin Elmer 983 FT-IR spec-
IR (KBr): 2984, 1738, 1698, 1646, 1588, 1567, 1462, 1367, 1278,
1020, 939, 909, 769 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
7.69 (d, J = 7.5 Hz, 1 H), 7.50–7.39 (m, 3 H), 7.33–7.24 (m, 3 H),
7.20–7.03 (m, 2 H), 6.47 (s, 0.5 H), 6.42 (d, J = 7.5 Hz, 0.5 H), 6.32
(d, J = 8.0 Hz, 0.5 H), 5.87 (s, 0.5 H), 5.84 (d, J = 8.0 Hz, 0.5 H),
5.74 (d, J = 7.5 Hz, 0.5 H), 4.51–4.36 (m, 2 H), 4.20–4.02 (m, 2 H),
1.44–1.37 (m, 3 H), 1.13–1.07 (m, 3 H).
1
trometer. H NMR (500 MHz) and 13C NMR (125 MHz) spectra
were recorded in CDCl3 on a Bruker Avance-500 spectrometer.
High-resolution mass spectra were obtained using an Agilent 5975l
instrument applying the electron spray ionization method.
Synthesis 2012, 44, 2519–2526
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Multicomponent Reactions in a Microreactor
2523
13C NMR (125 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
164.7, 164.4, 163.4, 162.9, 147.3, 143.3, 138.1, 136.8, 130.04,
129.96, 129.85, 129.5, 129.1, 128.9, 128.7, 128.3, 127.53, 127.47,
127.2, 126.1, 125.9, 125.44, 125.40, 125.1 (J = 288.8 Hz), 124.5
(J = 286.3 Hz), 124.4, 123.5, 111.8, 105.6, 105.2, 103.7, 82.9 (J =
30.0 Hz), 80.9, 80.3 (J = 28.8 Hz), 78.7, 63.10, 63.07, 61.4, 61.3,
14.1, 13.9, 13.8.
129.8, 129.6, 129.1, 129.0, 128.8, 128.4, 128.3, 127.6, 127.4, 127.2,
126.1, 125.8, 125.51, 125.46, 125.1 (J = 288.8 Hz), 124.5 (J = 285.0
Hz), 124.4, 123.4, 111.9, 105.9, 105.5, 103.2, 82.9 (J = 28.8 Hz),
80.9, 80.0 (J = 30.0 Hz), 78.7, 53.7, 52.4, 52.2.
HRMS (ESI): m/z [M]+ calcd for C23H18F3NO5: 445.1137; found:
445.1141.
HRMS (ESI): m/z [M]+ calcd for C25H22F3NO5: 473.1450; found:
473.1452.
Dimethyl 2-(4-Bromophenyl)-2-(trifluoromethyl)-2,11b-di-
hydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4e)
Yield: 42.8 mg (82%); yellow oil.
Diethyl 2-(4-Bromophenyl)-2-(trifluoromethyl)-2,11b-di-
hydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4b)
Yield: 44.7 mg (81%); yellow oil.
IR (KBr): 2953, 1747, 1646, 1567, 1494, 1462, 1429, 1400, 1319,
1282, 1110, 1010, 941, 910, 773, 733 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
7.63–7.57 (m, 2 H), 7.47–7.29 (m, 4 H), 7.23–7.06 (m, 2 H), 6.45
(s, 0.5 H), 6.41 (d, J = 8.0 Hz, 0.5 H), 6.31 (d, J = 8.0 Hz, 0.5 H),
5.89 (d, J = 8.0 Hz, 0.5 H), 5.84 (s, 0.5 H), 5.78 (d, J = 8.0 Hz, 0.5
H), 4.02 (s, 1.5 H), 3.96 (s, 1.5 H), 3.70 (s, 1.5 H), 3.66 (s, 1.5 H).
13C NMR (125 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
165.0, 164.7, 163.7, 163.1, 147.6, 143.5, 137.0, 135.9, 132.0, 131.5,
130.8, 130.2, 130.0, 129.7, 129.6, 129.2, 128.2, 127.7, 127.1, 125.8,
125.6, 125.4, 124.8 (q, J = 288.8 Hz), 124.3 (q, J = 286.3 Hz), 124.2,
123.6, 123.3, 123.2, 111.2, 106.2, 105.7, 102.4, 82.4 (q, J = 30.0
Hz), 81.0, 79.8 (q, J = 28.8), 78.7, 53.8, 52.4, 52.2.
IR (KBr): 2984, 1738, 1704, 1646, 1587, 1566, 1462, 1367, 1280,
1007, 941, 906, 772 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
7.61–7.56 (m, 2 H), 7.44–7.25 (m, 5 H), 7.13–7.05 (m, 1 H), 6.45
(s, 0.5 H), 6.41 (d, J = 7.5 Hz, 0.5 H), 6.32 (d, J = 7.5 Hz, 0.5 H),
5.86 (d, J = 7.5 Hz, 0.5 H), 5.84 (s, 0.5 H), 5.76 (d, J = 7.5 Hz, 0.5
H), 4.50–4.37 (m, 2 H), 4.20–4.04 (m, 2 H), 1.44–1.37 (m, 3 H),
1.14–1.10 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
164.5, 164.2, 163.3, 162.7, 147.7, 143.6, 137.2, 136.1, 131.9, 131.4,
130.8, 130.2, 130.0, 129.9, 129.8, 129.3, 128.2, 127.7, 127.2, 125.8,
125.7, 125.5, 124.9 (J = 288.8 Hz), 124.4 (J = 290.0 Hz), 124.2,
124.0, 123.3, 111.2, 105.9, 105.5, 102.9, 82.4 (J = 28.8 Hz), 81.0,
79.9 (J = 27.5 Hz), 78.7, 63.20, 63.17, 61.6, 61.4, 14.1, 13.93,
13.90.
HRMS (ESI): m/z [M]+ calcd for C23H17BrF3NO5: 523.0242; found:
523.0250.
Dimethyl 2-(4-Fluorophenyl)-2-(trifluoromethyl)-2,11b-di-
hydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4f)
Yield: 38.4 mg (83%); yellow oil.
HRMS (ESI): m/z [M]+ calcd for C25H21BrF3NO5: 551.0555; found:
551.0556.
IR (KBr): 2954, 1744, 1646, 1586, 1567, 1512, 1462, 1429, 1241,
1182, 1028, 946, 912, 837, 774 cm–1.
Diethyl 2-(4-Fluorophenyl)-2-(trifluoromethyl)-2,11b-di-
hydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4c)
Yield: 40.3 mg (82%); yellow oil.
1H NMR (500 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
7.70–7.68 (m, 1 H), 7.51–7.26 (m, 3 H), 7.23–7.13 (m, 2 H), 7.08–
6.99 (m, 2 H), 6.46 (s, 0.5 H), 6.41 (d, J = 7.5 Hz, 0.5 H), 6.30 (d, J
= 7.5 Hz, 0.5 H), 5.88 (d, J = 7.5 Hz, 0.5 H), 5.85 (s, 0.5 H), 5.77 (d,
J = 7.5 Hz, 0.5 H), 4.02 (s, 1.5 H), 3.96 (s, 1.5 H), 3.70 (s, 1.5 H),
3.65 (s, 1.5 H).
13C NMR (125 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
165.1, 164.8, 163.8, 163.3 (q, J = 248.8 Hz), 163.2, 162.9 (q, J =
247.5 Hz), 147.4, 143.3, 133.9, 132.5, 131.24, 131.18, 130.2, 130.0,
129.8, 129.7, 129.52, 129.46, 128.2, 127.7, 127.0, 126.1, 125.9,
125.7, 125.58, 125.55, 124.94 (q, J = 288.8 Hz), 124.93 (q, J =
288.8 Hz), 124.3, 123.33, 115.8 (d, J = 21.3 Hz), 115.3 (d, J = 22.5
Hz), 111.7, 106.1, 105.6, 102.8, 82.3 (q, J = 30.0 Hz), 81.0, 79.9 (q,
J = 28.8 Hz), 78.6, 53.8, 52.4, 52.3.
IR (KBr): 2986, 1732, 1646, 1557, 1511, 1463, 1433, 1368, 1279,
1016, 945, 841, 774 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
7.71–7.68 (m, 1 H), 7.50–7.41 (m, 2 H), 7.34–6.96 (m, 5 H), 6.46
(s, 0.5 H), 6.42 (d, J = 8.0 Hz, 0.5 H), 6.32 (d, J = 7.5 Hz, 0.5 H),
5.86 (d, J = 8.0 Hz, 0.5 H), 5.84 (s, 0.5 H), 5.75 (d, J = 7.5 Hz, 0.5
H), 4.50–4.36 (m, 2 H), 4.18–4.03 (m, 2 H), 1.44–1.37 (m, 3 H),
1.14–1.07 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
164.6, 164.3, 163.2 (q, J = 248.8 Hz), 162.8 (q, J = 246.3 Hz), 162.7,
147.5, 143.4, 134.1, 132.7, 131.22, 131.16, 130.1, 129.92, 129.90,
129.8, 129.6, 129.5, 128.2, 127.6, 127.1, 125.9, 125.7, 125.51,
125.48, 125.0 (J = 288.8 Hz), 124.43 (J = 283.8 Hz), 124.3, 123.4,
115.6 (q, J = 21.3 Hz), 115.2 (q, J = 21.3 Hz), 111.7, 105.8, 105.4,
103.2, 82.3 (q, J = 30.0 Hz), 80.9, 79.8 (q, J = 28.8 Hz), 78.6, 63.17,
63.13, 61.5, 61.3, 14.1, 13.9, 13.8.
HRMS (ESI): m/z [M]+ calcd for C23H17F4NO5: 463.1043; found:
463.1043.
Diethyl 6-Methyl-2-phenyl-2-(trifluoromethyl)-2,11b-di-
hydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4g)
Yield: 37.9 mg (78%); yellow oil.
HRMS (ESI): m/z [M]+ calcd for C25H21F4NO5: 491.1356; found:
491.1357.
IR (KBr): 2985, 1732, 1648, 1593, 1574, 1418, 1371, 1341, 1248,
1031, 944, 909, 751 cm–1.
Dimethyl 2-Phenyl-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxa-
zino[2,3-a]isoquinoline-3,4-dicarboxylate (4d)
Yield: 36.1 mg (81%); yellow oil.
1H NMR (500 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
7.72 (d, J = 8.0 Hz, 1 H), 7.48–7.13 (m, 8 H), 6.22 (s, 0.5 H), 5.91
(s, 0.5 H), 5.87 (s, 0.5 H), 5.83 (s, 0.5 H), 4.41–3.94 (m, 4 H), 2.09
(s, 1.5 H), 2.04 (s, 1.5 H), 1.37–1.24 (m, 4.5 H), 1.07 (t, J = 7.5 Hz,
1.5 H).
13C NMR (125 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
165.0, 164.7, 163.8, 163.6, 144.3, 138.7, 137.2, 136.8, 135.4, 135.0,
131.8, 130.1, 129.9, 129.2, 128.9, 128.8, 128.44, 128.34, 128.2,
128.0, 127.5, 127.2, 126.4, 126.2, 125.0, 124.9, 124.8, 124.7, 124.5
(q, J = 287.5 Hz), 124.4, 124.3, 123.9 (q, J = 286.3 Hz), 105.2,
105.1, 83.9, 82.9, 81.0 (q, J = 30.0 Hz), 79.6 (q, J = 28.8 Hz), 63.0,
62.9, 62.2, 61.8, 20.1, 19.9, 14.02, 13.97, 13.91, 13.7.
IR (KBr): 2953, 1744, 1715, 1645, 1586, 1567, 1462, 1428, 1281,
1249, 1186, 1028, 944, 909, 766 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
7.68 (d, J = 7.5 Hz, 1 H), 7.50–7.25 (m, 6 H), 7.20–7.03 (m, 2 H),
6.45–6.40 (m, 1 H), 6.28 (d, J = 8.0 Hz, 0.5 H), 5.86–5.85 (m, 1 H),
5.74 (d, J = 8.0 Hz, 0.5 H), 4.00 (s, 1.5 H), 3.94 (s, 1.5 H), 3.68 (s,
1.5 H), 3.62 (s, 1.5 H).
13C NMR (125 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
165.3, 164.9, 163.9, 163.3, 147.2, 143.2, 137.9, 136.7, 130.1, 129.9,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2519–2526

2524
M. Lei et al.
SPECIAL TOPIC
HRMS (ESI): m/z [M]+ calcd for C26H24F3NO5: 487.1607; found:
487.1604.
Dimethyl 2-(4-Bromophenyl)-6-methyl-2-(trifluoromethyl)-
2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxyl-
ate (4k)
Yield: 44.6 mg (83%); yellow oil.
Diethyl 2-(4-Bromophenyl)-6-methyl-2-(trifluoromethyl)-
2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxyl-
ate (4h)
IR (KBr): 2953, 1747, 1649, 1589, 1490, 1417, 1346, 1250, 1036,
990, 941, 906, 811, 735 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
7.59–7.54 (m, 2 H), 7.44–7.12 (m, 6 H), 6.15 (s, 0.5 H), 5.84 (d, J =
16.5 Hz, 1 H), 5.80 (s, 0.5 H), 3.86–3.60 (m, 6 H), 2.05–1.97 (m, 3
H).
13C NMR (125 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
165.2, 165.1, 164.2, 163.8, 144.8, 139.4, 136.1, 135.8, 134.9, 134.6,
132.8, 132.1, 131.6, 130.3, 130.1, 129.2, 128.9, 128.4, 128.0, 126.8,
126.6, 126.4, 124.8, 124.62, 124.58, 124.3 (q, J = 287.5 Hz), 123.8,
123.6 (q, J = 286.3 Hz), 123.5, 122.6, 105.9, 105.6, 84.0, 82.9, 80.9
(q, J = 28.8 Hz), 79.2 (q, J = 28.8 Hz), 53.7, 53.6, 53.1, 52.8, 20.0,
19.8.
Yield: 46.3 mg (82%); yellow oil.
IR (KBr): 2985, 1732, 1650, 1588, 1566, 1493, 1418, 1371, 1342,
1248, 1010, 942, 911, 814, 754 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
7.57 (s, 2 H), 7.44–7.32 (m, 3 H), 7.25–7.12 (m, 3 H), 6.17 (s, 0.5
H), 5.86 (s, 0.5 H), 5.83 (d, J = 7.5 Hz, 1 H), 4.40–3.95 (m, 4 H),
2.07 (s, 1.5 H), 2.00 (s, 1.5 H), 1.35–1.24 (m, 4.5 H), 1.07 (t, J = 7.5
Hz, 1.5 H).
13C NMR (125 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
164.8, 164.6, 163.7, 163.4, 144.8, 139.1, 136.3, 135.9, 135.2, 134.8,
132.8, 131.9, 131.6, 131.5, 130.2, 130.0, 129.3, 129.0, 128.4, 128.1,
127.2, 126.5, 126.3, 124.7, 124.6, 124.55, 124.52, 124.3 (q, J =
292.5 Hz), 123.7, 123.67 (q, J = 297.5 Hz), 123.4, 123.1, 105.5,
105.3, 83.9, 82.9, 80.54 (q, J = 30.0 Hz), 79.1 (q, J = 28.8 Hz), 63.1,
63.0, 62.3, 62.0, 20.1, 19.9, 14.02, 13.97, 13.93, 13.8.
HRMS (ESI): m/z [M]+ calcd for C24H19BrF3NO5: 537.0399; found:
537.0405.
Dimethyl 2-(4-Fluorophenyl)-6-methyl-2-(trifluoromethyl)-
2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxyl-
ate (4l)
HRMS (ESI): m/z [M]+ calcd for C26H23BrF3NO5: 565.0712; found:
565.0716.
Yield: 39.6 mg (83%); yellow oil.
Diethyl 2-(4-Fluorophenyl)-6-methyl-2-(trifluoromethyl)-
2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxyl-
ate (4i)
IR (KBr): 2953, 1739, 1649, 1604, 1574, 1512, 1418, 1346, 1249,
1185, 1036, 989, 912, 733 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
7.71–7.66 (m, 1 H), 7.47–7.44 (m, 1 H), 7.40–7.12 (m, 5 H), 7.00–
6.97 (m, 1 H), 6.17 (s, 0.5 H), 5.86 (s, 0.5 H), 5.82 (d, J = 11.0 Hz,
1 H), 3.86–3.60 (m, 6 H), 2.05–1.98 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
165.3, 165.1, 164.2, 163.9, 163.1 (d, J = 248.8 Hz), 163.0 (d, J =
247.5 Hz), 144.3, 139.1, 135.0, 134.7, 132.9, 132.5, 131.61, 131.57,
130.2, 130.1, 129.53, 129.46, 129.3, 129.2, 128.4, 128.0, 127.3,
126.6, 126.4, 125.6, 124.8, 124.7, 124.64, 124.60, 124.4 (q, J =
287.5 Hz), 123.7 (q, J = 285.0 Hz), 123.2, 115.9 (d, J = 22.5 Hz),
115.4 (d, J = 21.3 Hz), 105.7, 105.5, 83.9, 82.8, 80.6 (q, J = 30.0
Hz), 79.1 (q, J = 28.8 Hz), 53.7, 53.6, 53.1, 52.8, 20.0, 19.8.
Yield: 41.9 mg (83%); yellow oil.
IR (KBr): 2986, 1732, 1649, 1604, 1574, 1512, 1418, 1372, 1341,
1248, 1035, 941, 906, 837, 805 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:1.5 mixture of diastereoisomers) =
7.72–7.69 (dd, J = 7.5 Hz, 5.5 Hz, 1 H), 7.49–7.33 (m, 3 H), 7.27–
7.13 (m, 3 H), 7.00 (t, J = 8.5 Hz, 1 H), 6.20 (s, 0.6 H), 5.87 (s, 1 H),
5.84 (s, 0.4 H), 4.45–3.96 (m, 4 H), 2.09 (s, 1.2 H), 2.02 (s, 1.8 H),
1.37–1.26 (m, 5 H), 1.09 (t, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ (1:1.5 mixture of diastereoisomers) =
164.9, 164.7, 164.06, 163.95, 163.8, 163.5, 163.1 (q, J = 247.5 Hz),
163.0 (q, J = 247.5 Hz), 144.4, 138.9, 135.3, 134.9, 133.1, 132.6,
131.73, 131.70, 130.2, 130.0, 129.60, 129.54, 129.4, 129.3, 128.4,
128.1, 127.7, 126.5, 126.3, 125.6, 124.73, 124.66, 124.5, 124.4 (q,
J = 287.5 Hz), 123.8, 123.76 (q, J = 285.0 Hz), 115.7 (d, J = 21.3
Hz), 115.3 (d, J = 21.3 Hz), 105.3, 105.2, 83.9, 82.8, 80.5 (q, J =
30.0 Hz), 79.1 (q, J = 28.8), 63.1, 63.0, 62.3, 61.9, 20.1, 19.9, 14.04,
13.99, 13.93, 13.8.
HRMS (ESI): m/z [M]+ calcd for C24H19F4NO5: 477.1199; found:
477.1199.
Methyl 2-Phenyl-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazi-
no[2,3-a]isoquinoline-3-carboxylate (4m)
Yield: 11.6 mg (30%); red oil.
HRMS (ESI): m/z [M]+ calcd for C26H23F4NO5: 505.1512; found:
505.1515.
IR (KBr): 2952, 1698, 1614, 1568, 1494, 1456, 1424, 1316, 1266,
1024, 944, 909, 772, 734 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:3 mixture of diastereoisomers) =
7.98–7.96 (m, 1 H), 7.71–7.69 (d, J = 7.5 Hz, 1 H), 7.56–7.21 (m, 7
H), 7.03 (d, J = 7.5 Hz, 0.25 H), 6.98 (d, J = 7.5 Hz, 0.75 H), 6.63
(s, 0.25 H), 6.40 (d, J = 7.5 Hz, 0.25 H), 6.29 (d, J = 7.5 Hz, 0.75
H), 5.91 (s, 0.75 H), 5.73 (d, J = 7.5 Hz, 0.25 H), 5.63 (d, J = 7.5
Hz, 0.75 H), 3.80–3.61 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ (1:3 mixture of diastereoisomers) =
165.4, 164.7, 152.2, 147.3, 144.1, 143.1, 137.9, 137.1, 130.4, 129.6,
129.4, 129.1, 128.7, 128.1, 127.5, 127.4, 127.3, 126.9, 126.8, 126.7,
126.5, 126.4, 126.1, 125.24 (q, J = 290.0 Hz), 125.20, 124.3 (q, J =
285.0 Hz), 105.2, 104.8, 102.9, 101.4, 82.4 (q, J = 30.0 Hz), 80.3 (q,
J = 33.8 Hz), 80.2, 78.5, 51.6, 51.4.
Dimethyl 6-Methyl-2-phenyl-2-(trifluoromethyl)-2,11b-di-
hydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4j)
Yield: 37.2 mg (81%); yellow oil.
IR (KBr): 2953, 1738, 1648, 1596, 1574, 1497, 1417, 1346, 1249,
1032, 989, 943, 911, 802, 733 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
7.71 (d, J = 7.5 Hz, 1 H), 7.50–7.15 (m, 8 H), 6.22 (s, 0.5 H), 5.89
(d, J = 7.0 Hz, 1 H), 5.85 (s, 0.5 H), 3.89–3.62 (m, 6 H), 2.09–2.04
(m, 3 H).
13C NMR (125 MHz, CDCl3): δ (1:1 mixture of diastereoisomers) =
165.4, 165.1, 164.3, 164.0, 144.1, 138.9, 136.9, 136.6, 135.1, 134.7,
131.6, 130.1, 130.0, 129.3, 129.0, 128.9, 128.4, 128.1, 127.5, 127.3,
127.1, 126.5, 126.3, 124.8, 124.9, 124.7, 124.5 (q, J = 287.5 Hz),
123.8 (q, J = 286.3 Hz), 123.7, 105.6, 105.4, 83.9, 82.8, 81.0 (J =
30.0 Hz), 79.5 (q, J = 28.8 Hz), 53.6, 53.5, 53.0, 52.7, 20.0, 19.8.
HRMS (ESI): m/z [M]+ calcd for C21H16F3NO3: 387.1082; found:
387.1080.
Diethyl 2-Phenyl-2,11b-dihydro[1,3]oxazino[2,3-a]isoquino-
line-3,4-dicarboxylate (4o)
Yield: 7.3 mg (18%); yellow solid; mp 30–31 °C.
HRMS (ESI): m/z [M]+ calcd for C24H20F3NO5: 459.1294; found:
459.1293.
Synthesis 2012, 44, 2519–2526
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Multicomponent Reactions in a Microreactor
2525
IR (KBr): 2979, 1738, 1702, 1600, 1569, 1492, 1461, 1398, 1366,
1229, 1144, 1108, 1048, 771 cm–1.
References
(1) (a) Ganem, B. Acc. Chem. Res. 2009, 42, 463. (b) Toure, B.
B.; Hall, D. G. Chem. Rev. 2009, 109, 4439. (c) Dömling, A.
Chem. Rev. 2006, 106, 17. (d) Nair, V.; Rajesh, C.; Vinod,
A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal,
A. L. Acc. Chem. Res. 2003, 36, 899. (e) Zhu, J. P. Eur. J.
Org. Chem. 2003, 1133. (f) Dömling, A.; Ugi, I. Angew.
Chem. Int. Ed. 2000, 39, 3168.
(2) For reviews on microreactors, see: (a) Wiles, C.; Watts, P.
Chem. Commun. 2011, 47, 6512. (b) Wegnar, J.; Kirschning,
A.; Ceylan, S. Chem. Commun. 2011, 47, 4583. (c) Geyer,
K.; Gustafsson, T.; Seeberger, P. H. Synlett 2009, 2382.
(d) Hartman, R. L.; Jensen, K. F. Lab Chip 2009, 9, 2495.
(e) Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett
2008, 151. (f) Mason, B. P.; Price, K. E.; Steinbacher, J. L.;
Bogdan, A. R.; McQuade, D. T. Chem. Rev. 2007, 107,
2300. (g) Watts, P.; Haswell, S. J. Chem. Soc. Rev. 2005, 34,
235. (h) Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M.
Angew. Chem. Int. Ed. 2004, 43, 406.
1H NMR (500 MHz, CDCl3): δ (1:5.7 mixture of diastereoisomers) =
7.46–7.40 (m, 4 H), 7.39–6.96 (m, 5 H), 6.43 (d, J = 8.0 Hz, 0.15
H), 6.30 (d, J = 7.5 Hz, 0.85 H), 6.23 (s, 0.15 H), 5.97 (s, 0.15 H),
5.91 (s, 0.85 H), 5.74 (s, 0.85 H), 5.65 (d, J = 8.0 Hz, 1 H), 4.48–
4.45 (m, 2 H), 4.10–4.05 (m, 2 H), 1.44–1.41 (m, 3 H), 1.04–1.02
(m, 3 H).
13C NMR (125 MHz, CDCl3): δ (1:5.7 mixture of diastereoisomers)=
164.9, 164.6, 164.2, 163.7, 143.8, 143.2, 141.3, 139.7, 130.15,
130.08, 129.5, 129.4, 129.2, 128.5, 128.4, 128.3, 128.0, 127.2,
127.0, 126.9, 126.7, 125.2, 125.0, 124.10, 124.05, 110.2, 105.6,
104.2, 103.9, 83.1, 78.9, 77.9, 74.0, 62.8, 62.7, 60.6, 60.4, 14.3,
14.1, 13.9.
HRMS (ESI): m/z [M]+ calcd for C24H23NO5: 405.1576; found:
405.1579.
Diethyl 2-(4-Bromophenyl)-2,11b-dihydro[1,3]oxazino[2,3-
a]isoquinoline-3,4-dicarboxylate (4p)
Yield: 10.1 mg (21%); yellow solid; mp 47–48 °C.
(3) For example, see: (a) Salimi-Moosavi, H.; Tang, T.;
Harrison, D. J. J. Am. Chem. Soc. 1997, 119, 8716. (b) Wu,
T.; Mei, Y.; Cabral, J. T.; Xu, C.; Beers, K. L. J. Am. Chem.
Soc. 2004, 126, 9880. (c) Kawaguchi, T.; Miyata, H.; Ataka,
K.; Mae, K.; Yoshida, J. Angew. Chem. Int. Ed. 2005, 44,
2413. (d) Ducry, L.; Roberge, D. M. Angew. Chem. Int. Ed.
2005, 44, 7972. (e) Wiles, C.; Watts, P.; Haswell, S. J.;
Pombo-Villar, E. Tetrahedron 2005, 61, 10757. (f) Belder,
D.; Ludwig, M.; Wang, L.; Reetz, M. T. Angew. Chem. Int.
Ed. 2006, 45, 2463. (g) Wang, J.; Sui, G.; Mocharla, V. P.;
Lin, R. J.; Phelps, M. E.; Kolb, H. C.; Tseng, H. Angew.
Chem. Int. Ed. 2006, 45, 5276. (h) Miller, P. W.; Long, N. J.;
de Mello, A. J.; Vilar, R.; Passchier, J.; Gee, A. Chem.
Commun. 2006, 546. (i) Uozumi, Y.; Yamada, Y. M. A.;
Beppu, T.; Fukuyama, N.; Ueno, M.; Kitamori, T. J. Am.
Chem. Soc. 2006, 128, 15994. (j) Geyer, K.; Codée, J. D. C.;
Seeberger, P. H. Chem.–Eur. J. 2006, 12, 8434. (k) Sahoo,
H. R.; Kralj, J. G.; Jensen, K. F. Angew. Chem. Int. Ed. 2007,
46, 5704. (l) Mu, J. X.; Yin, X. F.; Wang, Y. G. Synlett 2005,
3163. (m) Hu, R.-J.; Lei, M.; Xiong, H.-S.; Mu, X.; Wang,
Y.-G.; Yin, X.-F. Tetrahedron Lett. 2008, 49, 387.
IR (KBr): 2979, 1738, 1700, 1599, 1569, 1461, 1397, 1367, 1273,
1230, 1145, 1110, 1049, 1010, 772 cm–1.
1H NMR (500 MHz, CDCl3): δ (1:5.7 mixture of diastereoisomers) =
7.56–7.54 (d, J = 8.5 Hz, 2 H), 7.41–6.96 (m, 6 H), 6.40 (d, J = 8.0
Hz, 0.15 H ), 6.30 (d, J = 7.5 Hz, 0.85 H), 6.23 (s, 0.15 H), 5.94 (s,
0.15 H), 5.86 (s, 0.85 H), 5.76 (d, J = 7.5 Hz, 0.15 H), 5.69–5.67 (m,
1.7 H), 4.52–4.31 (m, 2 H), 4.14–3.96 (m, 2 H), 1.44–1.40 (m, 3 H),
1.08–1.04 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ (1:5.7 mixture of diastereoisomers) =
164.8, 164.4, 164.0, 163.6, 144.1, 143.6, 140.5, 139.0, 131.8, 131.6,
131.0, 130.2, 130.1, 129.7, 129.6, 128.0, 127.3, 127.2, 126.7, 125.4,
125.1, 124.0, 122.7, 122.3, 109.7, 104.9, 104.5, 104.3, 83.2, 78.2,
78.0, 73.4, 63.0, 62.9, 60.8, 60.7, 14.2, 14.1, 14.0.
HRMS (ESI): m/z [M]+ calcd for C24H22BrNO3: 483.0681; found:
483.0692.
Diethyl 2-(4-Nitrophenyl)-2,11b-dihydro[1,3]oxazino[2,3-a]iso-
quinoline-3,4-dicarboxylate (4q)
Yield: 40.9 mg (91%); yellow solid; mp 55–56 °C.
IR (KBr): 2981, 1738, 1700, 1597, 1570, 1520, 1460, 1347, 1272,
1248, 1229, 1144, 1106, 1049, 852, 772 cm–1.
(n) McMullen, J. P.; Stone, M. T.; Buchwald, S. L.; Jensen,
K. F. Angew. Chem. Int. Ed. 2010, 49, 7076. (o) Hessel, V.;
Löwe, H. Chem. Eng. Technol. 2005, 28, 267. (p) Organ, M.
G.; Comer, E. J. Am. Chem. Soc. 2005, 127, 8160.
(q) Hübner, S.; Bentrup, U.; Budde, U.; Lovis, K.; Dietrich,
T.; Freitag, A.; Küpper, L.; Jähnisch, K. Org. Process Res.
Dev. 2009, 13, 952. (r) O’Brien, M.; Baxendale, I. R.; Ley,
S. V. Org. Lett. 2010, 12, 1596. (s) Wang, N.; Matsumoto,
T.; Ueno, M.; Miyamura, H.; Kobayashi, S. Angew. Chem.
Int. Ed. 2009, 48, 4744. (t) Popa, D.; Marcos, R.; Sayalero,
S.; Vidal-Ferran, A.; Pericàs, M. A. Adv. Synth. Catal. 2009,
351, 1539. (u) Petersen, T. P.; Ritzen, A.; Ulven, T. Org.
Lett. 2009, 11, 5134.
1H NMR (500 MHz, CDCl3): δ (1:1.5 mixture of diastereoisomers) =
8.30–8.14 (m, 2 H), 7.66–7.58 (m, 2 H), 7.41–7.09 (m, 3 H), 7.04–
6.93 (m, 1 H), 6.43 (d, J = 8.0 Hz, 0.4 H), 6.32 (d, J = 7.5 Hz, 0.6
H), 6.23 (s, 0.4 H), 6.06 (s, 0.4 H), 5.84 (s, 0.6 H), 5.81 (d, J = 7.5
Hz, 0.4 H), 5.78 (s, 0.6 H), 5.71 (d, J = 7.5 Hz, 0.6 H), 4.54–4.40
(m, 2 H), 4.16–3.96 (m, 2 H), 1.46–1.40 (m, 3 H), 1.09–1.05 (m, 3
H).
13C NMR (125 MHz, CDCl3): δ (1:1.5 mixture of diastereoisomers) =
164.5, 163.8, 163.43, 163.39, 148.1, 148.0, 147.9, 147.6, 144.7,
144.2, 130.2, 130.0, 129.9, 129.8, 129.5, 128.0, 127.4, 127.2,
126.43, 126.38, 125.6, 125.4, 123.9, 123.8, 123.7, 108.9, 104.9,
104.8, 103.9, 83.2, 78.5, 77.7, 73.0, 63.15, 63.08, 14.4, 14.2, 14.1.
(4) Huisgen, R.; Morikawa, M.; Herbig, K.; Brunn, E. Chem.
Ber. 1967, 100, 1094.
HRMS (ESI): m/z [M]+ calcd for C24H22N2O7: 450.1427; found:
(5) (a) Nair, V.; Sreekanth, A. R.; Abhilash, N.; Bhadbhade, M.
M.; Gonnade, R. C. Org. Lett. 2002, 4, 3575. (b) Nair, V.;
Rema Devi, B.; Varma, L. R. Tetrahedron Lett. 2005, 46,
5333. (c) Wang, G. W.; Li, J. X. Org. Biomol. Chem. 2006,
4, 4063. (d) Nair, V.; Sreekanth, A. R.; Biju, A. T.; Rath, N.
P. Tetrahedron Lett. 2003, 44, 729. (e) Esmaeili, A. A.
Nazer M. Synlett 2009, 2119. (f) Arizadeh, A.; Zohreh, N.
Synthesis 2008, 429. (g) Yavari, I.; Mirzaei, A.; Moradi, L.;
Hosseini, N. Tetrahedron Lett. 2008, 49, 2355. (h) Terzidis,
M. A.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J.
Synlett 2009, 229. (i) Shaabani, A.; Rezayan, A. H.; Sarvary,
A.; Heidary, M.; Ng, S. W. Tetrahedron 2009, 65, 6063.
450.1425.
Acknowledgment
Financial support of this work from the National Science Support
Program (No. 2012BAI13B06) and Natural Science Foundation of
Zhejiang Province (No. Y4100107) is gratefully acknowledged.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2519–2526

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M. Lei et al.
SPECIAL TOPIC
(8) For selected syntheses of heterocycles containing a
(j) Yavari, I.; Mirzaei, A.; Moradi, L.; Khalili, G.
Tetrahedron Lett. 2010, 51, 396.
trifluoromethyl group, see: (a) Abid, M.; Török, B. Adv.
Synth. Catal. 2005, 347, 1797. (b) Wang, X. N.; Shao, P. L.;
Lv, H.; Ye, S. Org. Lett. 2009, 11, 4029. (c) Zhu, J. T.; Chen,
Z. X.; Xie, H. B.; Li, S.; Wu, Y. M. Org. Lett. 2010, 12,
2434. (d) Wang, T.; Ye, S. Org. Lett. 2010, 12, 4168.
(e) Matoba, K.; Kawai, H.; Fukukawa, T.; Kusuda, A.;
Tokunaga, E.; Nakamura, S.; Shiro, M.; Shibata, N. Angew.
Chem. Int. Ed. 2010, 49, 5762.
(6) Huang, J. J.; Pan, W. L.; Xiao, Q. T.; Feng, M. H.; Wan, Y.
Q.; Ma, L.; Song, H. C. Acta Sci. Nat. Univ. Sunyatseni
2006, 45, 50.
(7) (a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (b) Purser,
S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320. (c) Ritter, T. Nature 2010, 466, 447.
Synthesis 2012, 44, 2519–2526
© Georg Thieme Verlag Stuttgart · New York