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Supporting Information

Schmidt Reaction of Ketones in DME solution

in a Continuous-Flow Microreactor

Yuesu Chen, Binjie Liu, Xiaofeng Liu, Yongtai Yang, Yun Ling, Yu Jia*

Department of Chemistry, Fudan University, Shanghai, 200433, P.R. China

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General Information

1HNMR spectra

13C-NMR spectra were recorded on JEOL ECA NMR spectrometer

(1H 400 MHz,

13C 100 MHz). HPLC analysis was performed on Agilent 1200 (DAD:

254nm; column: agilent zorbax eclipse XDB-C18 (4.6×150 mm, I.D. 5 µm); mobile

phase: MeOH-water, 10% to 90% MeOH within 6 min, flow rate 1.0 mL/min ). ESI

mass spectra were recorded on Bruker micro TOF II. All reagents were obtained from

commercial sources and used without further purification. Solvent DME was

pre-desiccated by sodium wires. The syringe pumps (ALC-IP 900) whose flow rate

ranges from 0.001mL/h to 27mL/min were purchased from Shanghai Alcott Biotech

Co., LTD. The stainless steel T-shaped micromixers (BUSHING JOINT 3WAY

JOINT 1/16 OTW), the PTFE tubes (1/16 × 0.75 cm × 5 m) and the back pressure

regulator (75psi) were purchased from Dikma Technology Co., Ltd. Each part of the

microreactor system was sealed with PEEK fittings (Standard Version 5/pkg).

HPLC determination of the yield of 3b: 0.750 mL of reaction mixture was collected

in a test tube with ice in it and then diluted to 25.00 mL by methanol. 10.0µL of this

solution was injected to the HPLC-instrument for analysis. Since the response factor

( area - mass concentration ) of 3a and 3b were found to be nearly equal ( 3a:3b =

1.09 ) and the amount of the impurity was negligibly small (<1%), the area percentage

of 3b was regarded as the mass fraction, which was then converted to the molar

fraction (yield). Retention time: 3a (7.4 min), 3b (6.6 min), impurity (6.4 min)

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Microreactor System

The continuous-flow microreactor system was constructed from the following parts:

two syringe pumps (P1 and P2), a T-shaped micromixer (M), PTFE tubing (including

microreactor R), an oil bath, a back pressure regulator (BPR) and collection devices.

The MsOH solution and the binary solution of ketone and tetrabutylammonium azide

(TBAA) ware fed in two streams, mixed in the T-shaped mixer (M), then entered the

microreactor (R, 500µL) heated in the oil bath at 80 ºC. After passing through the

back pressure regulator (BPR), the discharge was quenched and collected in a glass

vessel with ice in it. The product solution was poured into a beaker containing

crushed ice and neutralized with ammonia solution until pH=9, and then extracted

with CH2Cl2. The combined organic phase was dried over Na2SO4, filtered and

concentrated. The resulting crude product was purified by flash chromatography on

silica gel with hexane and AcOEt as eluent to afford the product amide.

For the scaled-up reaction, the reactants were fed by 50mL syringes, which are the

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largest ones our pumps permit. Hence, MsOH was fed by two syringe pumps (P11

and P12) joint by a second T-joint (M1). The rest parts of the microreactor system

were unvaried.

Experimental Data

The analytical data of Caprolactam (1b)1 N-Benzyl-2-phenyl-acetamide (2b)

2

N-Phenyl-acetamide (3b)3 N-(4-Methoxy-phenyl)-acetamide (4b)

3 N-(3-Methoxy

-phenyl)-acetamide (5b)4 N-(2-Methoxy-phenyl)-acetamide (6b)

5 N-p-Tolyl-

acetamide (7b)3 N-o-Tolyl-acetamide (8b)

3 N-(4-Chloro-phenyl)-acetamide (10b)

3

N-(3-Chloro-phenyl)-acetamide (11b)3 N-(4-Trifluoromethyl-phenyl)-acetamide

(13b)6 N-(3-Trifluoromethyl-phenyl)-acetamide (14b)

7 N-Naphthalen-2-yl-acetamide

(16b)8 2,N-Diphenyl-acetamide (18b)

9 Diphenylmethanone (19b)

1 5H-Phenanthridin-

6-one (20b)10

were identical to those reported in the literature.

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N-(4-Cyclohexyl-phenyl)-acetamide (9b) 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J =

8.4 Hz, 2H), 7.26 (s, 1H), 7.15 (d, J = 8.4 Hz, 2H), 2.46 (m, 1H), 2.16 (s, 3H), 1.90 –

1.69 (m, 4H), 1.46 – 1.17 (m, 6H). 13

C NMR (101 MHz, CDCl3) δ 168.18, 144.35,

135.48, 127.26, 120.10, 44.01, 34.49, 29.69, 26.88, 26.13, 24.49.

N-(6-Methoxy-naphthalen-2-yl)-acetamide (17b) 1H NMR (400 MHz, CDCl3) δ 8.07

(s, 1H), 7.68 (dd, J = 8.8, 2.5 Hz, 2H), 7.42 (dd, J = 8.8, 1.9 Hz, 1H), 7.31 (s, 1H),

7.13 (dd, J = 8.9, 2.5 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 3.91 (s, 3H), 2.22 (s, 3H). 13

C

NMR (101 MHz, CDCl3) δ 168.32, 157.20, 133.44, 129.13, 127.46, 120.47, 119.32,

117.08, 110.92, 105.72, 55.32, 24.66

References

(1) Kaur, G.; Rajput, J. K.; Arora, P.; Devi, N. Tetrahedron Lett. 2014, 55,

1136–1140

(2) Morimoto, H.; Fujiwara, R.; Shimizu, Y.; Morisaki, K.; Ohshima, T. Org. Lett.

2014, 16(7), 2018−2021

(3) Sun, X.; Wang, M.; Li, P.; Zhang, X.; Wang, L. Green Chem., 2013, 15, 3289

(4) Zhou, F.; Han, X.; Lu, X. Tetrahedron Lett. 2011, 52(36), 4681-4685

(5) Zhang, L.; Wang, W.; Wang, A.; Cui, Y.; Yang, X.; Huang, Y.; Liu, X.; Liu, W.;

Son, J.; Oji, H.; Zhang, T. Green Chem., 2013,15, 2680-2684

(6) Mizuta, S.; Stenhagen, I. S. R.; O’Duill, M.; Wolstenhulme, J.; Kirjavainen, A. K.;

Forsback, S. J.; Tredwell, M.; Sandford, G.; Moore, P. R.; Huiban, M.; Luthra, S. K.;

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Passchier, J.; Solin, O.; Gouverneur; V. Org. Lett. 2013, 15(11),2648–2651

(7) Mali, S. M.; Bhaisare, R. D.; Gopi, H. N.; J. Org. Chem. 2013, 78(11), 5550−5555

(8) Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2008, 73(7),

2894-2897

(9) Chen, Z.; Fu, R.; Chai, W.; Zheng, H.; Sun, L.; Lu, Q.; Yuan, R. Tetrahedron

2014, 70, 2237-2245

(10) Dubost, E.; Magnelli, R.; Cailly, T.; Legay, R.; Fabis, F.; Rault, S. Tetrahedron

2010, 66, 5008-5016

9b

1H-NMR

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13C-NMR

HRMS

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17b

1H-NMR

13C-NMR

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HRMS