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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
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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