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General Information: 1H and 13C NMR spectra were recorded on a JEOL ECX-600 and ECA-500

spectrometer spectrometer in CDCl3 unless otherwise noted. Tetramethylsilane (TMS)

and CDCl3 served as an internal standard (δ = 0 and 7.24) for 1H NMR, CDCl3 served as an internal standard (δ = 77.0) for 13C NMR and CFCl3 served as internal standard (δ = 0) for 19F NMR. IR spectra were measured with JASCO FT/IR-4200 spectrometer. High-performance liquid chromatography was carried out using following apparatuses; SHIMAZU DGU-20A3, LC-20AB, SIL-20A, CBM-20A, SPD-M20A and CTO-20A. High resolution mass spectrometry was carried out using JEOL JMS-T100LP (AccuTOF LC-plus). Optical rotations were measured by JASCO P-2100 Polarimeter. Preparative thin layer chromatography was carried out using glass plates with Wakogel B-5F (Wako Pure Chemical Industry Ltd.). Calcium chloride (anhydrous) was purchased from Wako Pure Chemical Industry Ltd. Amino silica gel (Chromatorex DM1020, 75-150) was purchased from Fuji Silysia Chemical Ltd., and the content of nitrogen was determined by elemental analysis (0.73 mmol/g). Aldehydes and nitromethane were purchased from Tokyo Chemical Industry Co., Ltd., Wako Pure Chemical Industry Ltd. or Aldrich Co., Ltd., and distilled before use. Nitobenzene derivatives were purchased from Aldrich Co., Ltd., Tokyo Chemical Industry Co., Ltd. or Wako Pure Chemical Industry Ltd. and used directly for the reactions. Toluene was purchased from Wako Pure Chemical Industry Ltd. as a dried solvent and used directly. o-Xylene was purchased from Wako Pure Chemical Industry Ltd. as a dried solvent. Water was purchased from Wako Pure Chemical Industry Ltd. as a distilled water. Celite (Celite® 545) was purchased from Kokusan Chemical Co., Ltd. Calcium chloride dihydrate (ACS reagent, 223506-25G) was purchased from Aldrich Co., Ltd. Polymer-supported anti-Ph2-pyridinebisoxazoline (PS-Pybox) was synthesized according to the literature method.1 Triethylamine was purchased from Tokyo Chemical Industry Co., Ltd. and distillated before use. Malonic acid methyl ester and ethyl ester were purchased from Tokyo Chemical Industry Co., Ltd. and purified by distillation. Dimethylpolysilane (DMPSi) was purchased from Nippon Soda Co., Ltd. and palladium acetate was purchased from Aldrich Co., Ltd. Acidic silica gel (Chromatorex ACD, COOH MB100-75/200, 0.38 mmol/g) was purchased from Fuji Silysia Chemical Ltd. All of the obtained nitroakenes (4),2 1,4-adducts (6),3 aniline derivatives,4 7a,5a rolipram (1),6, 7 and phenibut8 were literature-known, and all the physical data were compared

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with those in the literature, and the structures were confirmed. For apparatuses for the flow systems, we used HPLC pump (SHIMADZU LC 20AT x 3, 20AD), tube pump (MCRP204 with a controller prepared by Tokyo Rikakikai Co., LTD. (EYLA)), oven (SHIMADZU LC CTO-20AC or EYLA) and cooling bath (EYLA PSL-1000). EYLA Flow Master (CCR-1000G) was used for reduction of substrates 6.

Experimental procedure for synthesis of β-nitrostyrene 4 under continuous flow conditions (Figure S1, Scheme S1): A SUS (∅ 10 mm x 300 mm) with column ends equipped with filter was used for this system. A mixed silica-amine catalyst (Chromatorex DM1020 (Fuji Silysia) 4.5 g, 0.73 mmol/g) and finely crush calcium chloride (anhydrous, >95%, Wako pure chemical, 13.5 g) were introduced into this

column. Toluene was flowed into the column by plunger pump (for HPLC, 100 µL/min) to prepare catalyst slurry. The solution of aldehyde (2, 60 mmol), nitromethane (3, 50 mmol) and toluene (200 mL) was mixed in volumetric flask (200 mL), and then the

solution was flowed into the column (50 µL/min, 50-75 °C). After stabilization, the fraction was monitored in 1 h during the continuous flow, and the obtained solution was evaporated under vacuum and the yield was determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane, 1,2,4,5-tetramethylbenzene or 1,3,5-trimethoxybenzene as an internal standard.

Figure S1. Flow Reactor 1 (diagram).

I: Si-NH2/CaCl2 = 3/1 (18 g, ∅ 10 mm x 300 mm)

a: 50 µL/min

a

Si-NH2/CaCl2

ArCHO (0.2 M)CH3NO2 (0.25 M)

50-75 °C

Flow 1

I


SUPPLEMENTARY INFORMATIONRESEARCHdoi:10.1038/nature14343

Scheme S1. Synthesis of Nitoalkene 4a, b

a The flow reaction was continued without stop and >90% yields were kept at least for a week. The yield

was determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard. b As an independent experiment, when the flow reaction was stopped during weekend and restarted after

the break, it was confirmed that >90% yields were still kept.

When the reaction was conducted at 50 °C, >90% yields were obtained for ca. 100

h, but after that the yields were slightly decreased. On the other hand, the system was found to be stable at 75 °C in the reaction with benzaldehyde. Furthermore, we also confirmed that the reactions also proceeded with silica-amine (Chromatorex DM1020) alone without mixing with CaCl2. The stability of the system is better using the mixed silica-amine/CaCl2 catalyst.

Other nitroalkenes (4a-4i) were prepared under continuous flow conditions (Scheme S2).

O

ArCH3NO2+

FlowNO2

Si-NH2/CaCl250 µL/min75 °C, Tol

3, 0.24 M2, 0.2 M

4 (>90%)

MeOO



Scheme S2. Synthesis of Various Nitroalkenes

Experimental procedure for three-component asymmetric 1,4-addition reactions of malonate under continuous flow; synthesis of 1,4-adduct 6 (Figure S2, Scheme S3): The nitroakene synthesis system (Flow 1) and the asymmetric 1,4-addition system (Flow 2) were connected with valve. For the asymmetric 1,4-addition reaction, we

conducted as follow. Two glass columns (∅ 10 mm x 100 mm) were used. Celite® (1.4 g), calcium chloride dehydrate (Aldrich, 375 mg), and polymer-supported Pybox (0.85 mmol/g, 750 mg) were charged into the columns. For drying the substrates and a

triethylamine solution, a pre-column (∅ 5 mm x 50 mm) that contained dried activated MS 4A (500 mg), was connected between valve and the reaction columns. A nitroalkene 4 solution and malonate 5 with a triethylamine solution were mixed in the bottom of the column end. We prepared two reaction solutions; One (Reservoir 1) is aldehyde (2, 0.2 M) and nitromethane (3, 0.24 M) in toluene. Another (Reservoir 2) is malonate (5, 0.22 M) and triethylamine (0.016 M) in toluene. The solution of Reservoir 1 was introduced into the Column I at 50 mL/min and the solution of Reservoir 2 was

introduced into the Column X at 50 µL/min. The total flow rato was 100 µL/min at Column X and II. During the reactions, Column I was heated at 50 °C and Column II-1 and II-2 were cooled at 0 °C. First, we conducted the reaction to path A stabilization, and then, we changed to path B and start to flow the solution of Reservoir 2. After

O

RCH3NO2

FlowR NO2

Si-NH2/CaCl250 ∈…L/min

50 °C, Tol~36 h

3, 0.24 M2, 0.2 M

NO2 NO2

Meo-MeC6H4 (4b): quantm-MeC6H4 (4c): 98%p-MeC6H4 (4d): quant

NO2

Xp-FC6H4 (4f): 89%p-BrC6H4 (4g): 91%

NO2

MeO4e: 99%4a: quant

NO2O

4h: 92%

NO2

4i: 64%

+



stabilization, the fraction was collected in every 4 h during the continuous flow. The solid NH4Cl was added to the fraction and the mixture was diluted with dichromethane and was filtered. The obtained solution was evaporated under vacuum and analyzed by 1H NMR. The crude material was further purified by preparative TLC. The enantioselectivity of the obtained product was determined by HPLC analysis.

We confirmed that the use of Column X (MS 4A) was not essential. The same level of the yield and selectivity was obtained without Column X. We used Column X for stability of the whole system.



II-1, II-2: PS-Pybox–CaCl2/Celite® = 750/375/1400 (2.525 g, ∅ 10 mm x 100 mm)

X: MS 4A (500 mg, ∅ 5 mm x 50 mm)

a, b: 50 µL/min

a

Si-NH2/CaCl2

Reservoir 1ArCHO (2, 0.2 M)CH3NO2 (3, 0.24 M)in Tol

0 °C

PS-(S)-Pybox–CaCl2

Reservoir 2Malonate (5, 0.22 M)Et3N (0.016 M)in Tol

1

Loop

50 °C

Flow 1 Flow 2

b

A

B

I

II-1 II-2

Receiver 2Product (6)

X

Receiver 1



Scheme S3. Synthesis of Chiral γ-Nitro Ester 6.

Similarly, other chiral γ-nitro esters 6 were prepared under continuous flow conditions (Scheme S4).1

Scheme S4. Synthesis of Various γ-Nitro Esters

O

ArCH3NO2+

50 µL/minFlow 1

Ar NO2

Si-NH2/CaCl250 °C, Tol

3, 0.24 M2, 0.2 M100 µL/min (Total)

Flow 2

O

MeO

O

OMe

NO2

(5, 0.22 M)Et3N (0.016 M)

50 µL/min

4

6 (84%, 94% ee)

PS-PyboxCaCl2•2H2O

0 °C

O

MeO

O

OMe

MeOO

O

Ar

CH3NO2

+ 50 µL/minFlow 1

Ar NO2

Si-NH2/CaCl250 °C, Tol

3, 0.24 M

2, 0.2 M

100 µL/min (Total)Flow 2

O

R

O

OMe

ArNO2

(5, 0.22 M)Et3N (0.016 M)

50 µL/min

46

PS-PyboxCaCl2•2H2O–20-10 °C

O

R

O

OMe

~36 h

O

MeO

O

OMe

PhNO2

10 °C86%, 93% ee

O

MeO

O

OMe

NO210 °C

80%, 93% ee

O

MeO

O

OMe

NO210 °C

82%, 92% ee

O

MeO

O

OMe

NO20 °C

81%, 92% eeF

O

MeO

O

OMe

NO210 °C

72%, 92% ee

O

O

Me

O

OMe

PhNO2

–20 °C86%, 50/50 dr, 93/93% ee



Typical experimental procedure for hydrogenations of nitro compounds (Figure S3, Scheme S5): Hydrogenations of nitro compounds under continuous flow conditions were conducted using newly-prepared polysilane/activated carbon-supported palladium (Pd/(DMPSi-C), 0.29 mmol/g) as a catalyst. The new catalyst was prepared as follows: Bone ash (Charcoal, Bone; Wako Pure Chemical Industry Ltd.) was used as an activated carbon. DMPSi (dimethylpolysilane, 10 g) and carbon (bone black, 90 g) were combined in methyl alcohol under Ar. The solution was then cooled at 0 °C. Palladium acetate (20 mmol) was added to the mixture and the reaction mixture was heated gradually (over 40 min) at 70 °C. The reaction mixture was cooled to 0 °C and was filtrated. The obtained catalyst was washed with methyl alcohol, water, acetone and water successively. The crude catalyst was treated with citric acid (5%) and was stirred for 1 h at room temperature. The catalyst was then filtrated and washed with water to afford the desired Pd/(DMPSi-C) (Pd: 0.29 mmol/g (dry), ca. 32% wet). We also prepared similarly Pd/(DMPSi-C) (Pd: 0.13 mmol/g (dry), ca. 34% wet). The catalyst Pd/(DMPSi-C) (Pd: 0.13 mmol/g (dry), ca. 34% wet, 200 mg) and Celite® (200 mg)

were charged into a SUS column (∅ 5 mm x 50 mm). The flow rate was set at 100 µL/min. Hydrogen gas was generated from water using RHG-200 (Round science) and flowed at 5-7.5 mL/min. A column oven was set at 80 °C. A starting material (0.25-0.5 M, 3 mL) in ethyl alcohol was charged into the Reservoir and the hydrogenation was started. The Reservoir was washed with ethyl alcohol several times (1 mL x 3, 3 mL x 1) and was introduced into the column and then the column was washed with ethyl alcohol (>60 mL). The obtained solution was combined and ethyl alcohol was removed to afford the crude product. The yields were determined by 1H NMR analysis using an internal standard or isolation using preparative TLC (see below).

Several nitro compounds were subjected to the reduction, and in all cases the desired amino compounds were obtained in high yields (Scheme S5).



Figure S3. Flow Reactor of Hydrogenation (diagram).

Scheme S5. Hydrogenations of Nitro Compounds Using a New Catalyst: Substrate

Scope

Pump

Pd/DMPSi-C (Pd(dry): 0.13 mmol/g, 200 mg)Celite (200 mg)∅ 0.5 cm x 5 cm

ReservoirSM (0.25-0.5 M)

in EtOH

100 µL/min

ReceiverProduct

80 °C

H25 -7.5mL/min

Hydrogen Generator

Ar NO2 + H2 (5 mL/min)Pd/(DMPSi-C) (0.038 mmol)

EtOH, 80 °C100 µL/min

NH2ArFlow

NH2 NH2

o-: 82%a (1.5 mmol, 0.5 M)

p-: 93%a (1.5 mmol, 0.5 M)

m-: 81%b

(0.75 mmol, 0.25 M)p-: 86%a

(0.75 mmol, 0.25 M)

NH2

82%a

(1.5 mmol, 0.5 M)

NH2

O

NH2F

quanta,c (1.5 mmol, 0.5 M)

86%a (0.75 mmol, 0.25 M,

H2: 7.5 mL/min)

H2N

NH2HOCH2

NH2

MeO

72%a (0.75 mmol, 0.25 M,

H2: 7.5 mL/min)

NH2EtO

O

quanta (0.75 mmol, 0.25 M)

quant(0.75 mmol, 0.25 M)

Me



a Determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard. b Determined by 1H NMR analysis using 1,2,4,5-tetramethylbenzene as an internal standard. c Yield was determined after conversion to HCl salt. d Racemic form. e Isolated yield.

Experimental procedure for multistep flow synthesis of chiral γ-amino acid derivative 7 (Figure S4, Scheme S6): The nitroalkene synthesis system (Flow 1), the asymmetric 1,4-addition system (Flow 2), and the reduction system (Flow 3) were connected with valve. Flow 1 and Flow 2 were the same as the previously used systems.

For the reduction, we constructed the system as follows. Two SUS columns (∅ 10 mm x 100 mm) were used. Celite® (1.2 g) and Pd/(DMPSi-C) (Pd: 0.29 mmol/g (dry), ca. 32% wet, 4.8 g) were charged into the columns (Column III). The solution (the 1,4-adduct in toluene) and hydrogen gas (3 mL/min) were introduced into Column III-1 on the top of the column end. During the reactions, Column III was heated at 100 °C. First, we conducted the reaction using path A for stabilization, changed from path A to path B, and started the flow of the solution of Reservoir 2. After stabilization, the path was changed from C to D and the reduction was conducted. After stabilization, several fractions were collected during the continuous flow. The obtained solution was evaporated under vacuum, and then was purified by preparative TLC (ethyl acetate). The enantioselectivity of the obtained product 7 was determined by chiral HPLC analysis.5,7

Similarly, other chiral δ-lactams (7a-7f) were prepared under continuous flow

NO2+ H2 (7.5 mL/min)

NH2

O2N O2N

90%b (0.75 mmol, 0.25 M)

FlowPd/(DMPSi-C) (0.038 mmol)

EtOH, 80 °C100 µL/min

O

EtO

O

OEt

PhNO2

NH

OO

EtO

racd

(0.1 M, 0.3 mmol)

+ H2 (3 mL/min)Pd/(DMPSi-C) (0.067 mmol)

EtOH, 80 °C100 µL/min 94%e

Flow



conditions (Scheme 7).



II-1, II-2: PS-Pybox–CaCl2/Celite = 750/375/1400 (2.525 g, ∅ 10 mm x 100 mm)

III-1, III-2: Pd/DMPSi-C (1.824 mmol)/Celite = 4/1 (6 g, ∅ 10 mm x 100 mm)

X: MS 4A (500 mg, ∅ 5 mm x 50 mm)

a, b: 50 µL/min

Scheme S6. Multistep Continuous Flow Synthesis of Nitro Ester 7

a

Si-NH2/CaCl2


0 °C

PS-(S)-Pybox–CaCl2


1

Loop

50 °C

Flow 1 Flow 2 Flow 3

100 °Cb

2

Pd/DMPSi-C

A

B

C

D

Receiver 3Product (7)

H2

I

II-1 II-2 III-1 III-2X

Receiver 2Receiver 1

O

Ar

CH3NO2+ 50 µL/min

Flow 1

1. Si-NH2/ CaCl2 50 °C, Tol

3, 0.24 M100 µL/min (Total)

Flow 2

Methyl Malonate (5, 0.22 M)Et3N (0.016 M)

in Tol (50 µL/min) 2. PS-Pybox CaCl2•2H2O 0 °C2, 0.20 M

H2 (3 mL/min)

100 µL/min (Total)Flow 3

3. Pd/(DMPSi-C) 100 °C NH

OO

MeO

7 (74%, 94% ee)

MeO O

~24 h



Scheme S7. Multistep Continuous Flow Synthesis

(3R, 4S)-ethyl 2-oxo-4-phenylpyrrolidine-3-carboxylate (7a):5

IR (KBr, cm−1): 3250, 2983, 2900, 1739, 1700, 1493, 1446, 1372, 1336, 1273, 1166, 1050, 1024. 1H NMR (CDCl3, 600 MHz) δ: 7.32-7.18 (m, 5H), 4.19 (q, 2H, J = 7.1 Hz), 4.05 (q, 1H, J = 8.7 Hz), 3.77 (t, 1H, J = 8.9), 3.51 (d, 1H, J = 9.6 Hz), 3.38 (dd, 1H, J = 9.6, 8.3 Hz), 1.23 (t, 3H, J = 6.9 Hz).

13C NMR (CDCl3, 125 MHz) δ: 172.9, 169.2, 139.9, 128.9, 127.5, 126.9, 61.7, 55.3, 47.7, 44.3, 14.1. HR-MS (ESI, MeOH) m/z calcd. for C13H16NO3

+ ([M + H]+): 234.1125; found: 234.1118. HPLC Daicel Chiralpac AD3 x 2, hexane/iPrOH = 9/1, flow rate = 0.35 mL/min, Detection wavelength = 220 nm: tR = 83.9 min (minor), tR = 94.1 min (major).

[α]D33 +101 (c 0.50, CHCl3, 93% ee).

Elemental analysis calcd. For C13H15NO3: C, 66.94%; H, 6.48%; N, 6.00%; found: C,

O

Ar

CH3NO2+ 50 µL/min

Flow 1

1. Si-NH2/ CaCl2 50 °C, Tol

3, 0.24 M100 µL/min (Total)

Flow 2

Ethyl Malonate (5, 0.22 M)Et3N (0.016 M)

in Tol (50 µL/min) 2. PS-Pybox CaCl2•2H2O Temp2. 0.20 M

EtOH(100 µL/min)

H2 (5 mL/min)

200 µL/min (Total)Time

Flow 3

3. Pd/(DMPSi-C) 80 °C

NH

OO

EtO

Ar 7

NH

OO

EtO

7a0 °C

83%, 93% ee

NH

OO

EtO

7b0 °C

77%, 91% ee

NH

OO

EtO

7c0 °C

76%, 90% ee

F3C

NH

OO

EtO

7d0 °C

79%, 91% ee

F

NH

OO

EtO

7e0 °C

77%, 91% ee

NH

OO

EtO

7f10 °C

63%, 91% ee

S

NH

OO

EtO



66.77%; H, 6.62%; N, 5.89%. Ethyl 2-oxo-4-(m-tolyl)pyrrolidine-3-carboxylate (7b): IR (KBr, cm−1): 3314, 2967, 2888, 1727, 1682, 1605, 1489, 1432, 1377, 1327, 1258, 1208, 1173, 1114, 1051, 1018.

1H NMR (CDCl3, 600 MHz) δ: 7.21 (t, 1H, J = 7.6 Hz), 7.07 (d, 1H, J = 7.6 Hz), 7.03 (d, 2H, J = 8.3 Hz), 6.88 (s, 1H), 4.22 (q, 2H, J = 7.1 Hz), 4.04 (q, 1H, J = 8.7 Hz), 3.80-3.76 (m, 1H), 3.53 (d, 1H, J = 8.9 Hz), 3.40 (dd, 1H, J = 9.6, 8.3 Hz), 2.32 (s, 3H), 1.26 (t, 3H, J = 7.2 Hz).

13C NMR (CDCl3, 125 MHz) δ: 172.7, 169.2, 139.9, 138.7, 128.9, 128.3, 127.7, 123.9, 61.8, 55.2, 47.7, 44.3, 21.4, 14.1. HR-MS (ESI, MeOH) m/z calcd. for C14H18NO3+ ([M+H]+): 248.1281; found: 248.1271. HPLC Daicel Chiralpac AD-3, hexane/IPA = 9/1, flow rate = 0.25 mL/min, Detection wavelength = 220 nm: tR = 45.9 min (minor), tR = 53.8 min (major).

[α]D33 +109 (c 0.49, CHCl3, 92% ee).

Ethyl 2-oxo-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylate (7c):

IR (KBr, cm−1): 3277, 3006, 2959, 2899, 1741, 1719, 1690, 1618, 1446, 1334, 1271, 1217, 1177, 1120, 1052, 1016. 1H NMR (CDCl3, 600 MHz) δ: 7.59 (d, 2H, J = 8.3 Hz), 7.37 (d, 2H, , J = 8.1 Hz), 7.10 (brs, 1H), 4.24-4.21 (m, 2H), 4.15 (q, 1H, J = 8.7 Hz), 3.83 (t, 1H, J = 9.1 Hz), 3.52 (t, 1H, J = 9.6 Hz), 3.41 (dd, 1H, J = 9.7, 8.3 Hz), 1.26 (t, 3H, J = 7.1 Hz).

13C NMR (CDCl3, 125 MHz) δ: 172.2, 168.8, 143.9, 130.0 (q, J = 325 Hz), 127.4, 126.0 (q, J = 3.6 Hz), 123.9 (q, J = 272 Hz), 62.0, 55.0, 47.3, 44.0, 14.1. 19F NMR (CDCl3, 565 MHz) δ: –63.0. HRMS (ESI, MeOH) m/z calcd. for C14H14F3NNaO3+ ([M+Na]+): 324.0818; found: 324.0802. HPLC Daicel Chiralpac AD-3, hexane/IPA = 9/1, flow rate = 0.25 mL/min, Detection wavelength = 220 nm: tR = 43.9 min (minor), tR = 76.9 min (major).

[α]D33 +85.8 (c 0.50, CHCl3, 92% ee).

NH

OO

EtO

NH

OO

EtO

F3C



Dimethyl 2-(1-(4-fluorophenyl)-2-nitroethyl)malonate (7d): IR (KBr, cm−1): 3273, 2957, 2900, 1741, 1718, 1690, 1604, 1514, 1445, 1375, 1331,

1273, 1222, 1176, 1053, 1018. 1H NMR (CDCl3, 600 MHz) δ: 7.22-7.20 (m, 2H), 7.04-6.99 (m, 2H), 6.75 (brs, 1H), 4.24-4.20 (m, 2H), 4.06 (q, 1H, J = 8.7 Hz), 3.78 (t, 1H, J = 8.9 Hz), 3.47 (t, 1H, J = 9.6 Hz), 3.37 (t, 1H, J = 9.3 Hz), 1.26 (t, 3H, J = 7.2 Hz).

13C NMR (CDCl3, 125 MHz) δ: 172.3, 169.0, 162.1 (d, J = 247 Hz), 135.6 (d, J = 2.3 Hz), 128.6 (d, J = 8.1 Hz), 115.9 (d, J = 20.7 Hz), 61.9, 55.3, 47.6, 43.7, 14.1. 19F NMR (CDCl3, 565 MHz) δ: –115.0. HRMS (ESI, MeOH) m/z calcd. for C13H15FNO3+ ([M+H]+): 252.1030; found: 252.1025. HPLC Daicel Chiralcel OJ-3 + Daicel Chiralpac AD-3, hexane/IPA = 9/1, flow rate = 0.35 mL/min, Detection wavelength = 220 nm: tR = 94.0 min (minor), tR = 112.4 min (major).

[α]D33 +96.5 (c 0.50, CHCl3, 92% ee).

Ethyl 4-(naphthalen-2-yl)-2-oxopyrrolidine-3-carboxylate (7e):

IR (KBr, cm−1): 3257, 2996, 2948, 2890, 1739, 1718, 1686, 1444, 1364, 1315, 1271, 1209, 1174, 1120, 1054, 1018. 1H NMR (CDCl3, 600 MHz) δ: 7.70-7.66 (m, 3H), 7.57 (s, 1H), 7.36-7.32 (m, 2H), 7.23 (dd, 1H, J =8.3, 1.4 Hz), 6.89 (s, 1H), 4.13-4.09 (m, 3H,), 3.75 (t, 1H, J = 9.3 Hz), 3.53 (d, 1H, J = 9.6 Hz), 3.39 (d, 1H, J = 8.9 Hz), 1.13 (t, 3H, J = 6.9 Hz).

13C NMR (CDCl3, 125 MHz) δ: 172.9, 169.2, 137.2, 133.4, 132.7, 129.0, 127.7, 127.6, 126.5, 126.1, 125.9, 124.7, 61.8, 55.2, 47.6, 44.6, 14.1. HRMS (ESI, MeOH) m/z calcd. for C17H18NO3+ ([M+H]+): 284.1281; found: 284.1268. HPLC Daicel Chiralcel OJ-3 + Daicel Chiralpac AD-3, hexane/IPA = 9/1, flow rate = 0.5 mL/min, Detection wavelength = 220 nm: tR = 93.8 min (minor), tR = 107.7 min (major).

[α]D33 +124 (c 0.41, CHCl3, 92% ee).

NH

OO

EtO

F

NH

OO

EtO



Ethyl 2-oxo-4-(thiophen-2-yl)pyrrolidine-3-carboxylate (7f): IR (KBr, cm−1): 3253, 3106, 2986, 2921, 1732, 1705, 1673, 1487, 1446, 1395, 1365, 1337, 1272, 1245, 1202, 1179, 1095, 1059, 1017. 1H NMR (CDCl3, 600 MHz) δ: 7.19-7.19 (m, 1H), 6.93-6.91 (m, 3H), 4.35 (q, 1H, J =

8.7 Hz), 4.24 (q, 2H, J = 7.1 Hz), 3.82 (t, 1H, J = 8.6), 3.50 (d, 1H, J = 9.6 Hz), 3.45 (t, 1H, J = 8.9 Hz), 1.28 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 125 MHz) δ: 172.1, 168.7, 142.7, 127.1, 124.6, 124.4, 61.9, 56.2, 48.0, 40.0, 14.1. HRMS (ESI, MeOH) m/z calcd. for C11H14NO3S+ ([M + H]+):

240.0689; found: 240.0683. HPLC Daicel Chiralcel OJ-3 + Daicel Chiralpac AD-3, hexane/IPA = 9/1, flow rate = 0.25 mL/min, Detection wavelength = 220 nm: tR = 143.0 min (major), tR = 155.4 min (minor).

[α]D33 +90.2 (c 0.49, CHCl3, 92% ee).

Experimental procedure for multistep flow synthesis of (S)-rolipram (Figure S5, Scheme S8): The nitroalkene synthesis system (Flow 1), the asymmetric 1,4-addition system (Flow 2), the reduction system (Flow 3) and the decarboxylation system (Flow 4) were connected with valves. Flow 1 and Flow 2 were similar to the previously used

systems. For the reduction, we constructed the system as follows. A SUS column (∅ 10 mm x 200 mm) was used. Pd/(DMPSi-C) (Pd: 0.29 mmol/g (dry), ca. 32% wet, 10 g) and Celite® (2 g) were charged into the column (Column III). The solution (the 1,4-adduct in toluene, which comes from Column II) and hydrogen gas (3 mL/min) were introduced into Column III on the top of the column end. During the reaction, Column III was heated at 100 °C. The elution from Column III was introduced into the

Syringe Y (Amberlyst 15 Dry, 8 g). The reaction mixture (100 µL/min), water (10 µL/min) and o-xylene (100 µL/min) were mixed in the Celite® column (Column Z) and this solution was charged into the next column (Column IV, Si-COOH (Chromatorex ACD), 13.5 g, Celite® 0.5 g). Column IV was heated at 120 °C. We conducted the reaction using path A for stabilization, changed from path A to path B, and started the flow of the solution of Reservoir 2. After stabilization, the path was changed from C to D and the reduction was conducted. After stabilization, we switched from path E to path F and the flow was introduced into the Syringe Y. Then pumps c-e were started and the

NH

OO

EtO

S



solution was introduced into Column IV. After stabilization, several fractions were collected during the flow of the product solution. The obtained solution was evaporated under vacuum and was analyzed by 1H NMR, and then was purified by preparative TLC (ethyl acetate). (S)-Rolipram was obtained in 50% yield from 2 (997.8 mg/24 h, 96% ee). Recrystallization from water/methyl alcohol gave optically pure (S)-rolipram (>99% ee). Direct recrystallization of the crude product was also possible to obtain chemically and enantiomerically pure (S)-rolipram without chromatography. No palladium was contaminated, which was confirmed by Inductively Coupled Plasma analysis (less than detection limit (<0.01 ppm)). The enantioselectivity of the obtained product was determined by chiral HPLC analysis. The absolute configuration was determined by optical rotation.

For the synthesis of (R)-rolipram,6, 7 we used PS-(R)-Pybox (column II’) and other conditions were same as the synthesis of (S)-rolipram (1). (R)-Phenibut8 was also prepared from benzaldehyde using the same system.



II-1, II-2: PS-(R)-Pybox–CaCl2/Celite or PS-(S)-Pybox–CaCl2/Celite® = 750/375/1400 (2.525 g, ∅

10 mm x 100 mm)

III: Pd/DMPSi-C/Celite® = 5/1 (12 g, ∅ 10 mm x 200 mm)

IV: Si-COOH/Celite® = 27/1 (14 g, ∅ 10 mm x 300 mm)

X: MS 4A (500 mg, ∅ 5 mm x 50 mm)

Y: Amberlyst 15Dry (8 g)

Z: Celite® (ca. 350 mg, ∅ 5 mm x 50 mm)

75 °C

Si-NH2/CaCl2


0 °C

PS-Pybox–CaCl2


Flow 1 Flow 2 Flow 3

Pd

H2

100 °C

120 °C

Rolipram (1)

Flow 4

H2 Si-COOH

Z

a

b

c

d

e

A B C

D

E F

Reservoir 4o-Xylene

Reservoir 3H2O

1 2

3

I

II-1 II-2 III IVYX

Receiver 1 Receiver 2 Receiver 3



a, b: 50 µL/min

c, e: 100 µL/min

d: 10 µL/min

Scheme S8. Multistep Continuous Flow Synthesis of (S)-Roliparma

a The flow reaction was continued without stop for a week and the yield and the enantioselectivity were

kept. The yield was determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an internal

standard and the enantioselectivity was determined by chiral HPLC analysis.

(S)-4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one, (S)-rolipram (1):6

1H NMR (CDCl3, 500 MHz) δ: 6.80 (d, 1H, J = 8.5 Hz), 6.79-6.73 (m, 2H), 6.38 (brs, 1H), 4.76-4.72 (m, 1H), 3.80 (s, 3H), 3.73 (t, 1H, J = 8.8), 3.63-3.57 (m, 1H), 3.36 (dd, 1H, J = 9.4, 7.7 Hz), 2.68 (q, 1H, J = 8.7 Hz), 2.45 (q, 1H, J = 8.7 Hz), 1.94-1.76 (m, 6H), 1.63-1.53 (m, 2H). 13C NMR (CDCl3, 125 MHz) δ: 177.7, 149.1, 147.9, 134.5,

118.8, 113.8, 112.1, 80.5, 56.1, 49.7, 40.0, 38.0, 32.8, 24.0. HPLC Daicel Chiralpac AD-3, hexane/EtOH = 9/1, flow rate = 1.0 mL/min, Detection wavelength = 220 nm: tR = 13.8 min (majorr), tR = 18.5 min (minor).

[α]D15 = +37.1 (c 10.5, MeOH, 96% ee); Lit.6 [α]D

24 = +30.9 (c 0.5, MeOH, >99% ee (S)). References 1. Tsubogo, T. Yamashita, Y. Kobayashi, S. Chem. Eur. J. 2012, 18, 13624. 2. a) Mampreian, D. M.; Hoveyda, A. M. Org. Lett. 2004, 6, 2829. b) Trost, B. M.; Müller, C. J. Am. Chem. Soc. 2008, 130, 2438. c) Duursma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahedron, 2002, 58, 5773. 3. a) Ji, J.; Barnes, D.; Zhang, J.; King, S. A.; Wittenberger, S. J.; Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215.

CH3NO2+

50 µL/min

Flow 1

1. Si-NH2/CaCl2 75 °C, Tol

3, 0.12 M

100 µL/min (Total)

Flow 2

Methyl Malonate (5, 0.11 M)Et3N (0.016 M)

in Tol (50 µL/min) 2. PS-(S)-Pybox CaCl2•2H2O 0 °C

2, 0.1 M

H2 (3 mL/min)

100 µL/min (Total)

Flow 3

3. Pd/(DMPSi-C) (1.6 mmol) 100 °C

NH

OH2O (10 µL/min)o-Xylene (100 µL/min)4. HOOC-Silica Gel

120 °C

210 µL/min (Total)

Flow 4

MeOO

O

MeO O

(S)-Rolipram50%, 96% ee

NH

O

MeO

O



b) Barnes, D.; Ji, J.; Fickes, M. J.; Fitzgerald, M. A.; King, S. A.; Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J. Am. Chem. Soc. 2002, 124, 13097. c) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. d) Li, H.; Wang, Y.; Tang, L, Deng, L. J. Am. Chem.Soc. 2004, 126, 9906. e) Watanabe, M.; Ikagawa, A.; Wang, H.; Murata, K.; Lkariya, T. J. Am. Chem. Soc. 2004, 126, 11148. f) Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958. g) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. h) Li, H.; Wang, Yi, Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem. Int. Ed. 2005, 44, 105. i) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481. j) McCooey, S. H.; Connon, S. J. Angew. Chem. Int. Ed. 2005, 44, 6367. k) Miyake, H.; Tuchida, S.; Yamauchi, M.; Takemoto, Y. Synthesis 2006, 3295. l) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454. m) Barnes, D.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.; Morton, H. E.; Lattanzi, A. Tetrahedron: Asymmetry 2006, 17, 837. n) Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583. o) Chen, F-X.; Shao, C.; Wang, Q.; Gong, P.; Zhang, D.-Y.; Zhang, B.-Z.; Wang, R. Tetrahedron Lett. 2007, 48, 8456. 4. Most of aniline derivatives were purchased from Aldrich Co., Ltd. as authentic samples for determination of the product structures. See also; Kim, J.; Chang, S. Chem. Commun. 2008, 3052. 5. Wang, J.; Li, W.; Liu, Y.; Chu, Y.; Lin, L.; Liu, X.; Feng, X. Org. Lett. 2010, 12, 1280. 6. Baures, P. W.; Eggleston, D. S.; Erhard, K. F.; Cieslinski, L. B.; Torphy, T. J.;

Christensen, S. B. J. Med. Chem. 1993, 36, 3274.

7. Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.; Morton, H.;

Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J. Am. Chem.

Soc. 2002, 124, 13097.

8. Lapin, I. CNS Drug Rev. 2001, 7, 471.



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