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Synthesis 2012; 44(16): 2519-2526
DOI: 10.1055/s-0031-1290809
special topic
© Georg Thieme Verlag Stuttgart · New York

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

Ming Lei*
a   Department of Chemistry, Zhejiang University, 310027 Hangzhou, P. R. of China, Fax: +86(571)87951895   Email: 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   Email: hzhang21@gmail.com
,
Wan Tian
a   Department of Chemistry, Zhejiang University, 310027 Hangzhou, P. R. of China, Fax: +86(571)87951895   Email: leiming@zju.edu.cn
,
Ruijun Hu
a   Department of Chemistry, Zhejiang University, 310027 Hangzhou, P. R. of China, Fax: +86(571)87951895   Email: leiming@zju.edu.cn
,
Wei Li
a   Department of Chemistry, Zhejiang University, 310027 Hangzhou, P. R. of China, Fax: +86(571)87951895   Email: leiming@zju.edu.cn
,
Hong Zhang*
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   Email: hzhang21@gmail.com
c   Department of Nuclear Medicine, Second Affiliated Hospital of Zhejiang University, School of Medicine, 310009 Hangzhou, P. R. of China
› Author Affiliations
Further Information

Publication History

Received: 18 February 2012

Accepted: 05 March 2012

Publication Date:
08 May 2012 (online)

 
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Abstract

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.


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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 complicated skeletons in a one-pot manner, without the isolation of intermediates, and thereby greatly enhances the synthetic efficiency. As multicomponent reactions combine two major principles of organic synthesis – convergence 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 reactions.[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, efficient mixing and increased thermal transfer. The use of microreactors also enables the precise control of reactive intermediates and thereby facilitates highly selective reactions which can be difficult to achieve using conventional methods. By conducting multicomponent reactions in a microreactor, the advantages of both techniques can be combined such that reaction screening and optimization of the conditions would become more convenient. The process would be facilitated by continuous-flow conditions 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 heterocycles via the reaction of a 1,4-dipolar intermediate, generated­ from an isoquinoline and an acetylenedicarboxylate, with a dipolarophile such as phenyl isocyanate, diethyl­ mesoxalate, or dimethyl azodicarboxylate.[ 4 ] Following Huisgen’s pioneering contributions, cycloadditions 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 between the 1,4-dipolar intermediate and the acetylenedicarboxylate can occur to generate the cycloaddition by-product, 11bH-pyrido[2,1-a]isoquinoline-1,2,3,4-tetracarboxylate, along with suppression of the desired cycloaddition 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 dipolarophile, by virtue of the excellent mixing of reagents. Our previous work demonstrated the efficient acylation of ferrocene with various acid anhydrides using a microfluidic chip reactor; the yields and selectivities were improved 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 cycloaddition between an isoquinoline, a dialkyl acetylenedicarboxylate and 2,2,2-trifluoro-1-phenylethanone (3a), in high efficiency and selectivity compared with a typical batch system. The introduction of the electron-withdrawing trifluoromethyl group activates the ketones as dipolarophiles in the 1,4-dipolar cycloaddition reaction. Moreover, compounds containing a trifluoromethyl group have shown applications in medicinal chemistry.[7] [8]

In order to transfer the cycloaddition reaction to a continuous-flow microreactor, preliminary solvent screening was conducted in a batch flask system using the model reaction between isoquinoline (1a), diethyl acetylenedicarboxylate (2a) and 2,2,2-trifluoro-1-phenylethanone (3a) in a 1:1.1:1.1 molar ratio. At 20 °C, the progress of the cycloadditions in dichloromethane, tetrahydrofuran, 1,4-dioxane, ethanol, acetonitrile and toluene were evaluated by thin-layer chromatography (TLC). A comparatively high isolated yield (54%) of 2-(trifluoromethyl)-2H-[1,3]oxazino[2,3-a]isoquinoline 4a was obtained in acetonitrile which was accompanied with the expected by-product, tetraethyl 11bH-pyrido[2,1-a]isoquinoline-1,2,3,4-tetracarboxylate (5) in 20% yield.

Zoom Image
Scheme 1 Three-component 1,4-dipolar cycloaddition reaction in a batch flask system

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 syringes, a water bath, a Y-shaped mixer and stainless steel tubing and fittings (Figure [1]). Solution A [isoquinoline (1a) in acetonitrile (0.1 M)] and solution B [an equimolar mixture of 2a and trifluoro-phenylethanone 3a in acetonitrile (0.11 M)] were introduced into the mixer unit at identical flow rates using the syringe pump. The mixture was then allowed to flow through a stainless steel tube reactor (Ø = 500 μm, l = 1.5 m) which was submerged in a water bath. The outlet solution was collected and the yields were quantified using high-performance liquid chromatography (HPLC).

Zoom Image
Figure 1 Schematic of the continuous-flow system

The model reaction was investigated using the continuous-flow system by varying the flow rate (2, 4, 6 or 8 μL/min) and the temperature. Preliminary testing was performed at 20 °C. Yields of 86–88% of 4a (determined by HPLC) were obtained which were significantly higher than that achieved from the batch process at the same temperature. Moreover, the by-product 5 was not present according to liquid chromatography–mass spectrometry (LC–MS). The dramatic effect of the microflow system would appear to be attributable to the extremely rapid and efficient mixing of reagents by virtue of the short diffusion path in the micromixer. Encouraged by these results, we next examined the reaction at 30 °C which resulted in slightly increased yields of 4a (88–90%). When the temperature was raised to 50 °C, the reaction afforded 86%, 95%, 92% and 93% yields corresponding to the above 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.

For comparative purposes the model reaction was also carried out in a batch flask at 50 °C, in a one-pot manner over two hours. The yield of product 4a was 41% and that of by-product 5 increased to 34% (Scheme [2]). This result indicated that at higher temperatures the rate of the side reaction increased, whilst the extent of the desired cycloaddition was reduced. In the microreactor, the flow process enables continuous generation and in situ consumption of the intermediate formed between isoquinoline (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 cascade transformation proceeded at a much faster rate compared to the batch system.

Zoom Image
Scheme 2 A comparative one-pot model reaction in a batch flask system

Table 1 Three-Component 1,4-Dipolar Cycloaddition in a Flow Microreactor

Entry

Isoquinoline (R1)

Alkyne (R2/R3)

Carbonyl compound (R4/R5)

Product

Yield (%)a

 1

1a (H)

2a (CO2Et/CO2Et)

3a (CF3/H)

4a

79

 2

1a

2a

3b (CF3/Br)

4b

81

 3

1a

2a

3c (CF3/F)

4c

82

 4

1a

2b (CO2Me/CO2Me)

3a (CF3/H)

4d

81

 5

1a

2b

3b (CF3/Br)

4e

82

 6

1a

2b

3c (CF3/F)

4f

83

 7

1b (Me)

2a

3a (CF3/H)

4g

78

 8

1b

2a

3b (CF3/Br)

4h

82

 9

1b

2a

3c (CF3/F)

4i

83

10

1b

2b

3a (CF3/H)

4j

81

11

1b

2b

3b (CF3/Br)

4k

83

12

1b

2b

3c (CF3/F)

4l

83

13

1a

2c (H/CO2Me)

3a (CF3/H)

4m

30

14

1a

2a

3d (CH3/H)

4n

–

15

1a

2a

3e (H/H)

4o

18

16

1a

2a

3f (H/Br)

4p

21

17

1a

2a

3g (H/NO2)

4q

91

a Yield of isolated product based on isoquinoline 1.

In order to investigate the scope and limitations of this three-component cascade reaction exploiting the micro­reactor, a series of 2-(trifluoromethyl)-2H-[1,3]oxazino[2,3-a]isoquinolines 4a–m was prepared using the optimized conditions. The results are summarized in Table [1]. With highly active dialkyl acetylenedicarboxylates 2a and 2b, the presence of substituents on the isoquinoline 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 dipolarophiles under the optimized conditions, the electronic effects of which were quite apparent. For inactive acetophenone (3d), no trace of the desired product was detected (Table [1], entry 14). Benzaldehydes gave slightly better results (Table [1], entries 15 and 16), however, when the benzaldehyde was activated with a strong electron-withdrawing nitro group, an excellent 91% yield of the corresponding cycloadduct 4q was obtained (Table [1], entry 17).

Zoom Image
Scheme 3 Proposed mechanism

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 compound 3 to generate the [4+2] cycloaddition product 4 (Scheme [3]).

In conclusion, we have developed a three-component 1,4-dipolar cycloaddition reaction of isoquinolines 1, acetylenedicarboxylates 2 and 2,2,2-trifluoro-1-phenylethanone (3a) in a continuous-flow microreactor. Under the optimized conditions, a series of 2-(trifluoromethyl)-2H-[1,3]oxazino[2,3-a]isoquinoline derivatives was synthesized in 78–83% isolated yields. The process was also applied 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 reagents associated with the flow technique eliminated the formation of the by-product 5 and ensured that the cascade transformation proceeded with very high selectivity and efficiency.

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. Infrared spectra were recorded on a Perkin Elmer 983 FT-IR spectrometer. 1H 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.


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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). The mixture was stirred at r.t. for 10 h and then evaporated under vacuum. The residue was subjected to silica gel column chromatography (eluent: PE–EtOAc, 1:4) to give the product 4a (127.7 mg, 54%) and by-product 5 (46.9 mg, 20%).


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Tetraethyl 11bH-Pyrido[2,1-a]isoquinoline-1,2,3,4-tetracarboxylate (5)

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.

HRMS (ESI): m/z [M]+ calcd for C25H27NO8: 469.1737; found: 469.1743.


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Three-Component Cycloaddition in a Flow Microreactor; General 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 syringes 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.


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Diethyl 2-Phenyl-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4a)

Yield: 37.4 mg (79%); yellow oil.

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).�

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.�

HRMS (ESI): m/z [M]+ calcd for C25H22F3NO5: 473.1450; found: 473.1452.


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Diethyl 2-(4-Bromophenyl)-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4b)

Yield: 44.7 mg (81%); yellow oil.

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 C25H21BrF3NO5: 551.0555; found: 551.0556.


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Diethyl 2-(4-Fluorophenyl)-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4c)

Yield: 40.3 mg (82%); yellow oil.

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 C25H21F4NO5: 491.1356; found: 491.1357.


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Dimethyl 2-Phenyl-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4d)

Yield: 36.1 mg (81%); yellow oil.

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, 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.


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Dimethyl 2-(4-Bromophenyl)-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4e)

Yield: 42.8 mg (82%); 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.�

HRMS (ESI): m/z [M]+ calcd for C23H17BrF3NO5: 523.0242; found: 523.0250.


#

Dimethyl 2-(4-Fluorophenyl)-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4f)

Yield: 38.4 mg (83%); yellow oil.

IR (KBr): 2954, 1744, 1646, 1586, 1567, 1512, 1462, 1429, 1241, 1182, 1028, 946, 912, 837, 774 cm–1.

��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.�

HRMS (ESI): m/z [M]+ calcd for C23H17F4NO5: 463.1043; found: 463.1043.


#

Diethyl 6-Methyl-2-phenyl-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4g)

Yield: 37.9 mg (78%); yellow oil.

IR (KBr): 2985, 1732, 1648, 1593, 1574, 1418, 1371, 1341, 1248, 1031, 944, 909, 751 cm–1.

��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.�

HRMS (ESI): m/z [M]+ calcd for C26H24F3NO5: 487.1607; found: 487.1604.


#

Diethyl 2-(4-Bromophenyl)-6-methyl-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4h)

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 C26H23BrF3NO5: 565.0712; found: 565.0716.


#

Diethyl 2-(4-Fluorophenyl)-6-methyl-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4i)

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 C26H23F4NO5: 505.1512; found: 505.1515.


#

Dimethyl 6-Methyl-2-phenyl-2-(trifluoromethyl)-2,11b-dihydro[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 C24H20F3NO5: 459.1294; found: 459.1293.


#

Dimethyl 2-(4-Bromophenyl)-6-methyl-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3,4-dicarboxylate (4k)

Yield: 44.6 mg (83%); yellow oil.

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.�

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-dicarboxylate (4l)

Yield: 39.6 mg (83%); yellow oil.

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.�

HRMS (ESI): m/z [M]+ calcd for C24H19F4NO5: 477.1199; found: 477.1199.


#

Methyl 2-Phenyl-2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-3-carboxylate (4m)

Yield: 11.6 mg (30%); red oil.

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.�

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]isoquinoline-3,4-dicarboxylate (4o)

Yield: 7.3 mg (18%); yellow solid; mp 30–31 °C.

IR (KBr): 2979, 1738, 1702, 1600, 1569, 1492, 1461, 1398, 1366, 1229, 1144, 1108, 1048, 771 cm–1.

��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.

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]isoquinoline-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.

��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.

HRMS (ESI): m/z [M]+ calcd for C24H22N2O7: 450.1427; found: 450.1425.


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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.



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Zoom Image
Scheme 1 Three-component 1,4-dipolar cycloaddition reaction in a batch flask system
Zoom Image
Figure 1 Schematic of the continuous-flow system
Zoom Image
Scheme 2 A comparative one-pot model reaction in a batch flask system
Zoom Image
Scheme 3 Proposed mechanism