supporting info 04oct2017 final · e-mail : [email protected] e-mail:...

S1

SUPPORTING INFORMATION

High Throughput Mechanochemistry: Application to Parallel Synthesis of Benzoxazines.

Katia Martina,1 Laura Rotolo,1 Andrea Porcheddu,2 Francesco Delogu,3 Stephen R. Bysouth,4

Giancarlo Cravotto,1,* Evelina Colacino1,5*

1Dipartimento di Scienza e Tecnologia del Farmaco, University of Turin, via P. Giuria 9, Turin,

10125, Italy

2 Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, Cittadella

Universitaria, SS 554 bivio per Sestu, 09028 Monserrato (Ca), Italy

3 Dipartimento di Ingegneria Meccanica, Chimica, e dei Materiali, Università degli Studi di Cagliari,

via Marengo 2, 09123 Cagliari, Italy 4 Automaxion SARL, L’Auvrairie, 50250 Varenguebec, France 5 Université de Montpellier, Institut des Biomolécules Max Mousseron (IBMM) UMR5247 CNRS-

UM-ENSCM, Université de Montpellier, cc1703, Place Eugène Bataillon, 34095 Montpellier Cedex

05, France

*e-mail : [email protected]

*e-mail: [email protected]

General Remarks and Experimental Procedures S1

General procedure for the mechanochemical synthesis of compounds 1-14 (Scheme 1)

S1

General procedure for the synthesis of compounds 6 and 7 under conventional conditions (Scheme 1 and Table 1).

S2

General procedure for the synthesis of compound 14 under conventional conditions (Scheme 1 and Table 1)

S3

Multiposition jars for parallel synthesis (Figure S1). S4 1H NMR, 13C NMR and GC/MS spectra of compounds 1-14 (Scheme 1 and Figures S2-S43)

S5-S30

References S33

Electronic Supplementary Material (ESI) for ChemComm.This journal is © The Royal Society of Chemistry 2017

S2

General Remarks and Experimental Procedures

All chemicals were purchased from Sigma-Aldrich (solvents from Carlo Erba SpA) and used without

further purification. Reactions were monitored by TLC on Merck 60 F254 (0.25 mm) plates, which

were visualized by UV inspection and/or by heating after a spraying with 5% H2SO4 in ethanol or

phosphomolybdic acid. Merck silica gel was used for column chromatography (CC). NMR spectra

were recorded on a NMR Jeol ECZ-R (600 MHz and 150 MHz for 1H and 13C, respectively) at 25

°C. Chemical shifts (δ) of 1H NMR and 13C NMR spectra are reported in parts per million (ppm)

relative to residual solvent signals (CHCl3 in CDCl3: δ = 7.26 ppm for 1H and CDCl3: δ = 77.04 ppm

for 13C NMR), J values are given in Hz. The ball-milling experiments were performed in Automaxion

single position P6 mill at 550 rpm, using 8- or 12-multiposition jars hosting 20 mL (with 60 glass

balls 3 mm Æ in each vial) and 2 mL glass vials (with 60 stainless steel beads 1 mm Æ in each vial)

respectively. For the preparation of compound 1 and 2, the ball-milling experiments were performed

in a MM400 vibrational ball mill (Retsch GmbH, Haan, Germany) using 5 mL stainless steel jar (2

stainless steel balls, 5 mm Ø) or a PM100 planetary mill (Retsch GmbH, Haan, Germany) using a 45

mL zirconia jar (11 zirconia balls, 12 mm Ø). GC–MS analyses were performed in a GC Agilent 6890

(Agilent Technologies, USA) that was fitted with a mass detector Agilent Network 5973, using a 40

m long capillary column, i.d. of 0.25 mm and film thickness 0.25 µm (MEGA-MS). GC conditions

were: injection split 1:20, injector temperature 250 °C, detector temperature 280 °C. Gas carrier:

helium (1.2 mL/min), temperature program: from 50 °C (3 min) to 300 °C at 10 °C/min. Compounds

1-7, 11 and 13 display the same spectral characteristics of previously reported structures in the

literature (see Table 1 for references). Each compound was prepared twice: the reaction scale was

0.531 mmol for 2 mL glass vials and 3.186 mmol for 20 mL glass vials.

General procedure for the mechanochemical synthesis of compounds 1-14 (Scheme 1 and Table

1). The alcohol (1.0 equiv), the amine (1.0 equiv) and paraformaldehyde (4.0 equiv) were added to a

2 mL glass vials containing 60 stainless steel balls (Ø 1 mm). The vial was placed in a 12 position-

jar and the reactants were milled at 550 rpm for 4 hours, till complete conversion of starting materials

(TLC: c-Hex/AcOEt 98:2 v/v). The crude was recovered by CHCl3 (15 mL) and washed with aqueous

KOH 3M (15 mL). The organic layer was washed three times with water, dried over anhydrous

MgSO4 and concentrated. The crude compounds 1-14 were purified by column chromatography

(linear gradient of EtOAc in cyclohexane: 0-1%). A 8 position-jar was used to perform the reaction

in a 20 mL glass vials, (with 60 glass balls 3 mm Æ in each vial). Only for the preparation of

compound 3, HO-PEG-2000-OH (450 mg/mmol of substrate) was used as additive.1

S3

General procedure for the synthesis of compounds 6 and 7 under conventional conditions

(Scheme 1 and Table 1). To a solution of the aniline (11 mmol) in chloroform, paraformaldehyde

(0.66 g, 22 mol) was added and stirred for 15 min at 0 °C. Subsequently, 55 mmol of phenol or 2-

allyl phenol were added to the reaction mixture and stirred overnight at 60 °C. After completion of

the reaction, it was extracted with ethyl acetate and washed with 2 N NaOH, water, brine and the

organic layer concentrated to yield pale yellow liquid. The crude compounds were purified by column

chromatography (linear gradient of EtOAc in cyclohexane: 0-1%).

Synthesis of compounds 14 under conventional conditions (Scheme 1 and Table 1). To a solution

of the p-methoxy aniline (11 mmol) in toluene, paraformaldehyde (0.66 g, 22 mol) was added and

stirred for 15 min at 0 °C. Subsequently, 55 mmol of 2-allyl phenol were added and the 50 mL two-

necked flask connected to a Dean-Stark apparatus. The reaction mixture was brought to reflux and

left under stirring for 5 hrs. After completion of the reaction, it was extracted with ethyl acetate and

washed with 2 N NaOH, water, brine and the organic layer concentrated to yield pale yellow liquid.

The crude compounds were purified by column chromatography (linear gradient of EtOAc in

cyclohexane: 0-1%).

S4

a) b)

c)

Figure S1. 4-slot milling for a) 4-position jars with 200 mL glass vials; b) 8-position jars with 20 mL glass vials; 4-position jars with polyethylene (HDPE) vials c) (Pictures were kindly provided by Automaxion, www.automaxionltd.com).

S5

3,4-Dihydro-3-(4-nitrophenyl)-1,3-2H-benzoxazine, 1 (Scheme 1 and Table 1). CAS [117483-13-3]2

Yellow powder (61 mg, 45%); 1H NMR (600 MHz, CDCl3) δ (ppm): 4.74 (s, 2 H), 5.41 (s, 2 H), 6.86 (d, J = 8 Hz, 1 H), 6.93 - 6.96 (t, J = 8 Hz, 1 H), 7.06 (m, 3 H), 7.13 (t, J = 8 Hz, 1 H), 8.16 (d, J =9.31 Hz, 2 H); 13C NMR (150 MHz, CDCl3)2 δ (ppm): 49.51 (C-5), 78.59 (C-6), 115.08 (C-9, C-13), 117.31 (C-1), 120.13 (C-8), 121.61 (C-3), 125.85 (C-10, C-12), 126.77 (C-4), 128.36 (C-2), 140.43 (C-11), 152.92 (C-14), 154.03 (C-7); GC-MS (EI), m/z calcd for C14H12N2O3 256.08 found 256, 150, 134, 120, 106, 78, 51, 39; Rt = 32.615 min

LR122-F1-15_Proton-1-1.esp

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0Chemical Shift (ppm)

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5.41

6.856.95

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8.15

Figure S2. 1H NMR of 3,4-Dihydro-3-(4-nitrophenyl)-1,3-2H-benzoxazine 1

S6

LR122-F1-15_Carbon-1.asc

160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40Chemical Shift (ppm)

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115.

08

78.6

5

49.5

1

Figure S3. 13C NMR of 3,4-Dihydro-3-(4-nitrophenyl)-1,3-2H-benzoxazine, 1

Figure S4. MS (EI) of 3,4-Dihydro-3-(4-nitrophenyl)-1,3-2H-benzoxazine, 1

S7

3,4-Dihydro-3-(4-methoxyphenyl)-1,3-2H-benzoxazine, 2 (Scheme 1 and Table 1) CAS [51892-02-5]2, 3

White powder (83 mg, 65%); 1H NMR (600 MHz, CDCl3) δ (ppm): 3.73 (s, 3 H, H-15), 4.54 (s, 2 H, CH2-5) 5.28 (s, 2 H, CH2-6) 6.80 (m, 3 H, CH-10, CH-12, CH-1), 6.88 (t, J = 8 Hz, 1 H, CH-3), 6.99 (d, J = 8 Hz, 1 H, CH), 7.07 (d, J = 9 Hz, 2 H), 7.11 (t, J = 8 Hz, 1 H); 13C NMR (150 MHz, CDCl3)2 δ (ppm): 51.20 (C-15), 55.57 (C-5), 80.81 (C-6), 114.57 (C-9, C-13), 116.92 (C-1), 120.82 (C-12, C-10), 120.84 (C-3), 120.98 (C-8), 126.81 (C-2), 127.91 (C-4), 142.42 (C-14), 154.43 (C-11) 155.05 (C-7); GC-MS (EI), m/z calcd for C15H15NO2 241,11 found 241, 135, 120, 92, 78, 65, 51, 39. Rt = 29.182 min

LR 102.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5Chemical Shift (ppm)

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7.11

7.07

6.89 6.

886.

81

5.28

4.54

3.73

Figure S5. 1H NMR of 3,4-Dihydro-3-(4-methoxyphenyl)-1,3,2H-benzoxazine, 2

S8

LR 102_carbon.esp

180 160 140 120 100 80 60 40 20Chemical Shift (ppm)

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44

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9312

6.83

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116.

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4.59

80.8

377

.34

77.1

276

.91

55.5

951

.22

Figure S6. 13C NMR of 3,4-Dihydro-3-(4-methoxyphenyl)-1,3-2H-benzoxazine, 2

Figure S7. MS (EI) of 3,4-Dihydro-3-(4-methoxyphenyl)-1,3-2H-benzoxazine, 2

S9

3,4-Dihydro-3-(4-bromophenyl)-1,3-2H-benzoxazine, 3 (Scheme 1 and Table 1) CAS [100542-25-4]3, 4

White powder (102 mg, 67%); 1H NMR (600 MHz, CDCl3) d (ppm): 4.61 (s, 2 H, PhCH2N), 5.33 (s, 2 H, NCH2O), 6.82 (dd, J = 8 Hz, 1 H), 6.91 (t, J = 8 Hz, 1 H), 6.98 - 7.03 (m, 3 H), 7.13 (t, J = 8 Hz, 1 H), 7.37 (d, J = 9 Hz, 2 H); 13C NMR (150 MHz, CDCl3) d (ppm): 50.55 (C-5), 79.19 (C-6), 113.99 (C-11), 116.92 (C-1), 119.97 (C-9, C-13), 120.56 (C-8), 120.99 (C-3), 126.71 (C-4) 128,04 (C-2) 132.1 (C-10, C12), 147.47 (C-14), 154.14 (C-7); GC-MS (EI), m/z calcd for C14H12BrNO 289.01 found 289, 183, 154, 78, 51, 39; Rt = 30.089 min

LR103_Proton-2-1.esp


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377.

35

7.15

7.13

7.01

6.99

6.91

6.82

6.81

5.33

4.61

Figure S8. 1 H NMR of 3,4-Dihydro-3-(4-bromophenyl)-1,3-2H-benzoxazine, 3

S10

LR103_Carbon-1-1 (1).jdf

152 144 136 128 120 112 104 96 88 80 72 64 56 48 40Chemical Shift (ppm)

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1012

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6.71

120.

9911

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116.

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3.87

79.1

9

50.5

5

Figure S9. 13C NMR of 3,4-Dihydro-3-(4-bromophenyl)-1,3-2H-benzoxazine, 3

Figure S10. MS (EI) of 3,4-Dihydro-3-(4-bromophenyl)-1,3-2H-benzoxazine, 3

S11

3,4-Dihydro-3-(4-tolyl)-1,3-2H-benzoxazine, 4 (Scheme 1 and Table 1) CAS [51891-99-7]2, 3

Yellow-orange powder (78 mg, 65%); 1H NMR (600 MHz, CDCl3) d (ppm): 2.26 (s, 3H), 4.60 (s, 2 H), 5.33 (s, 2H), 6.80 (dd, J = 8 Hz, 1 Hz, 1H), 6.88 (td, J = 8 Hz, 1 Hz, 1H), 6.99 - 7.03 (m, 3H), 7.06 (d, J = 9 Hz, 2H), 7.11 (td, J = 8 Hz, 1 Hz, 1H); 13C NMR (150 MHz, CDCl3)2d (ppm): 20.53 (C-15), 50.63 (C-5), 80.02 (C-6), 116.90 (C-1), 118.71 (C-9, C-13), 120.79 (C-3), 126.73 (C-4), 127.84 (C-2), 129.79 (C-10, C-12) 131.28 (C-11), 145.89 (C-14), 154.27 (C-7); GC-MS (EI), m/z calcd for C15H15NO 225.29 found 225, 119, 91, 78, 65, 51, 39. Rt = 27.8 min

LR125_Proton-1-1 (1).esp

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0Chemical Shift (ppm)

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7.11

7.07

7.06

(12,

16) 7.

03(1

3,15

)7.

016.

99 6.88

(9)

6.80

5.33

(2)

4.60

(4)

2.26

(17)

Figure S11. 1H NMR of 3,4-dihydro-3-(4-tolyl)-1,3-2H-benzoxazine, 4

S12

LR125_Carbon-1.asc


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9.79

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6.73

120.

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116.

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80.0

2

50.6

3

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Figure S12. 13C NMR of 3,4-dihydro-3-(4-tolyl)-1,3-2H-benzoxazine, 4

Figure S13. MS (EI) of 3,4-dihydro-3-(4-tolyl)-1,3-2H-benzoxazine, 4

S13

3,4-Dihydro-3-phenyl-1,3-2H-benzoxazine, 5 (Scheme 1 and Table 1) CAS [51287-17-3]2, 3

Yellow oil (81 mg, 73%); 1H NMR (600 MHz, CDCl3) d (ppm): 4.64 (s, 2 H), 5.37 (s, 2H), 6.81 (dd, J = 7.4 Hz, 1 Hz, 1H), 6.89 (td, J = 6.9 Hz, 1.3 Hz, 1H), 6.94 (tt, J = 7.4 Hz, 1.3 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 7.11-7.13 (m, 3H), 7.26-7.29 (m, 2H); 13C NMR (150 MHz, CDCl3)2 d (ppm): 50.39 (C-5), 79.44 (C-6), 116.93 (C-1), 118.24 (C-9, C-13), 120.78 (C-11), 120.87 (C-8) 121.41 (C-3), 126.71 (C-4), 127.83 (C-2), 129.25 (C-10, C-12) 148.37 (C-14), 154.27 (C-7); GC-MS (EI), m/z calcd for C14H13NO 211.26 found 211, 105, 77, 51, 39; Rt= 26.778 min

LR117-F6-9_Proton-1-1.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5Chemical Shift (ppm)

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7.29

7.27

7.26

7.13 7.11

7.03 7.

026.

946.

896.

836.

81

5.37

4.64

Figure S14. 1H NMR of 3,4-dihydro-3-phenyl-1,3-2H-benzoxazine, 5

S14

LR117-F6-9_Carbon-1.asc


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4

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9

Figure S15. 13C NMR of 3,4-dihydro-3-phenyl-1,3-2H-benzoxazine, 5

Figure S16. MS (EI) of 3,4-dihydro-3-phenyl-1,3-2H-benzoxazine, 5

S15

3,4-Dihydro-3-benzyl-1,3-2H-benzoxazine, 6 (Scheme 1 and Table 1) CAS [128707-70-0]2

White powder (90 mg, 75%); 1H NMR (600 MHz, CDCl3) δ (ppm): 3.93 (s, 2H), 3.97 (s, 2H), 4.88 (s, 2H), 6.82 (d, J = 8.3 Hz, 1H), 6.87 (td, J = 7.6 Hz, J = 14.3 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.27-7.3 (m, 1H), 7.34-7.37 (m, 4H). 13C NMR (150 MHz, CDCl3) δ (ppm): 49.70 (C-5), 55.62 (C-9), 82.26 (C-6), 116.53 (C-1), 120.03 (C-8), 120.76 (C-3), 127.5 (C-2), 127.77 (C-4), 127.71 (C-13), 128.56 (C-14, C12), 129.08 (C-11, C15), 138.15 (C-10), 154.19 (C-7). GC-MS (EI), m/z calcd for C15H15NO 225.29 found 225, 134, 118, 107, 91, 78, 65, 51, 39 Rt = 27.008 min.

LR126NEW_Proton-1-1 (3).jdf


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88 6.87

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6.83

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3.93

Figure S17. 1H NMR of 3,4-dihydro-3-benzyl-1,3-2H-benzoxazine, 6

S16

LR126NEW_Carbon-1.asc

160 150 140 130 120 110 100 90 80 70 60 50 40 30Chemical Shift (ppm)

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Figure S18. 13C NMR of 3,4-dihydro-3-benzyl-1,3-2H-benzoxazine, 6

Figure S19. MS (EI) of 3,4-dihydro-3-benzyl-1,3-2H-benzoxazine, 6

S17

3,4-Dihydro-8-allyl-3-(4-tolyl)-1,3-2H-benzoxazine, 7 (Scheme 1 and Table 1)

Orange liquid (71 mg, 50%); 1H NMR (600 MHz, CDCl3) δ (ppm): 2.27 (s, 3H), 3.34 (d, J = 6.5 Hz, 2H), 4.59 (s, 2H), 5.02-5.05 (m, 2H), 5.35 (s, 2H), 5.94-6.00 (m, 1H), 6.82 (t, J =7.6 Hz, 1H), 6.87 (d, J = 7 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H). 13C NMR (150 MHz, CDCl3) δ (ppm): 20.5 (C-15), 33.64 (C-16), 50.88 (C-5), 79.80 (C-6), 115.39 (C-18) 118.59 (C-9, C-13), 120.22 (C-3), 120.44 (C-8), 124.72 (C-4), 127.98(C-1) 128.06 (C-2), 129.73 (C-12, C-10), 130.92 (C-11), 136.41 (C-17), 146.16 (C-14), 152.97(C-7); GC-MS (EI), m/z calcd for C18H19NO 265.15 found 265, 145, 131, 119, 91, 65, 51, 39; Rt = 29.830 min

LR132NEW_Proton-1-1.jdf


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96 5.95

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5.05

5.05 5.

025.

025.

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3.34

3.33

2.27

Figure S20. 1H NMR of 3,4-Dihydro-8-allyl-3-(4-tolyl)-1,3-2H-benzoxazine, 7

S18

LR132NEW_Carbon-1.asc


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Figure S21. 13C NMR of 3,4-Dihydro-8-allyl-3-(4-tolyl)-1,3-2H-benzoxazine, 7

Figure S22. MS (EI) of 3,4-Dihydro-8-allyl-3-(4-tolyl)-1,3-2H-benzoxazine, 7

S19

3,4-Dihydro-3-(2-iodophenyl)-1,3-2H-benzoxazine, 8 (Scheme 1 and Table 1)

White powder (137 mg, 77%); 1H NMR (600 MHz, CDCl3) d (ppm): 4.52 (s, 2 H), 5.24 (s, 2H), 6.80 (td, J = 7.5 Hz, 1.6 Hz, 1H), 6.87 (dd, J = 8.0 Hz, 1.0 Hz, 1H), 6.92 (td, J = 7.4 Hz, 1.3 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.21 (td, J = 8 Hz, 1.6 Hz, 1H), 7.36 (dd, J = 8 Hz, 1.6 Hz, 1H), 7.86 (dd, J = 7.7 Hz, 1.3 Hz, 1H). 13C NMR (150 MHz, CDCl3) d (ppm): 51.65 (C-5), 81.05 (C-6), 96.86 (C-13), 116.89 (C-1), 120.63 (C-8), 120.98 (C-3), 123.41 (C-9), 126.23 (C-11), 126.67 (C-4), 128.03 (C-2), 129.27 (C-10), 139.93 (C-12), 150.77 (C-14), 154.09 (C-7). GC-MS (EI), m/z calcd for C14H12INO 337.00 found 337, 231, 210, 202, 180, 77, 51. Rt = 29.821 min

LR145-f8-12_Proton-1-1.esp

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5Chemical Shift (ppm)

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6.88

6.87 6.

81

6.80

5.24

4.52

Figure S23. 1H NMR of 3,4-dihydro-3-(2-iodophenyl)-1,3-2H-benzoxazine, 8

S20

LR145-f8-12_Carbon-1.asc


0

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0.4

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0.6

0.7

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ized

Inte

nsity

154.

0915

0.77

139.

93 129.

27

126.

2312

3.41

120.

9812

0.63

116.

89

96.8

6

81.0

5

51.6

5

Figure S24. 13C NMR of 3,4-dihydro-3-(2-iodophenyl)-1,3-2H-benzoxazine, 8

Figure S25. MS (EI) of 3,4-dihydro-3-(2-iodophenyl)-1,3-2H-benzoxazine, 8

S21

3,4-Dihydro-8-allyl-3-(2-iodophenyl)-1,3-2H-benzoxazine, 9 (Scheme 1 and Table 1)

White powder (86 mg, 43%); 1H NMR (600 MHz, CDCl3) δ (ppm): 3.39 (d, J = 6.7 Hz, 2H), 4.53 (s, 2H), 5.05-5.09 (m, 2H), 5.27 (s, 2H), 6.00-6.06 (m, 1H), 6.84 (td, J = 7.5 Hz, 1.6 Hz, 1H), 6.87-6.88 (m, 2H), 7.05 (td, J = 7.4 Hz, 1.3 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.35 (dd, J = 7.8 Hz, 1.6 Hz, 1H), 7.87 (dd, J = 7.7 Hz, 1.3 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ (ppm): 33.66 (C-15), 51.81 (C-5), 81.01 (C-6), 96.86 (C-13), 115.41 (C-17), 120.17 (C-8), 120.45 (C-3), 123.41 (C-9), 124.65 (C-4), 126.14 (C-11), 127.94 (C-1), 128.15 (C-2), 129.21 (C-10), 136.71 (C-16), 139.88 (C-12), 150.86 (C-14), 151.76 (C-7); GC-MS (EI), m/z calcd for C17H16INO 377.03 found 377, 231, 202, 146, 131, 115, 91, 77, 51, 39. Rt = 31.74 min

LR146_1H.txt


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

7.88

7.88 7.

877.

86 7.36

7.36

7.35

7.34

7.23

7.21

7.20

7.05

7.04

6.88

6.87

6.81

6.81

6.80

6.06 6.

056.

046.

036.

026.

016.

00

5.27

5.09

5.08

5.08

5.07 5.07

5.06

5.05

4.53

3.40

3.39

Figure S26. 1H NMR of 3,4-Dihydro-8-allyl-3-(2-iodophenyl)-1,3-2H-benzoxazine, 9

N

OI

12

3

4 5

678

910

11

1213

14

1516

17

S22

LR146-f2-16_Carbon-1.asc

152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

151.

7615

0.86

139.

8813

8.94

136.

7113

6.65

129.

2112

8.15 12

6.14

124.

6512

3.41

120.

4512

0.17

115.

41

96.8

7

81.0

1

51.8

1 33.6

6

Figure S27. 13C NMR of 3,4-Dihydro-8-allyl-3-(2-iodophenyl)-1,3-2H-benzoxazine, 9

Figure S28. 1H NMR of 3,4-Dihydro-8-allyl-3-(2-iodophenyl)-1,3-2H-benzoxazine, 9

S23

3,4-Dihydro-8-allyl-3-(4-nitrophenyl)-1,3-2H-benzoxazine, 10 (Scheme 1 and Table 1)

White powder (36 mg, 23%); 1H NMR (600 MHz, CDCl3) δ (ppm): 3.33 (d, J = 6.7 Hz, 2H), 4.72 (s, 2H), 5.01-5.04 (m, 2H), 5.42 (s, 2H), 5.92-5.96 (m, 1H), 6.88 (t, J = 7 Hz, 1H), 6.93 (d, J = 7 Hz, 1H), 7.02 (d, J = 7 Hz, 1H), 7.04 (d, J = 9.3 Hz, 2H), 8.15 (d, J = 9.3 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ (ppm): 33.66 (C-15), 49.58 (C-5), 114.94 (C-13, C-9), 115.85 (C-17), 119.82 (C-8), 121.35 (C-3), 124.85 (C-4), 125.95 (C-12, C-10), 128.73 (C-2), 136.41 (C-16), 140.39 (C-11), 151.9 (C-14), 152.97(C-7). GC-MS (EI), m/z calcd for C17H16N2O3 296.1 found 296, 145, 131, 120, 117, 91, 77, 65, 51, 39. Rt = 34.330 min

LR133-f17,23,25,32,33_Proton-1-1.esp


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

Nor

mal

ized

Inte

nsity

8.16 8.

15

7.06

7.04

7.03

6.90 6.

896.

88

5.96 5.95

5.94

5.92

5.42

5.04

5.04

5.02

5.01

4.72

3.34

3.33

Figure S29. 1H NMR of 3,4-dihydro-8-allyl-3-(4-nitrophenyl)-1,3-2H-benzoxazine, 10

S24

LR133-f17,23,25,32,33_Carbon-1.asc


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

Nor

mal

ized

Inte

nsity

152.

9715

1.90

140.

3913

6.41 12

8.73

125.

9512

4.85

121.

3511

5.85

114.

94

49.5

8

33.6

6

Figure S30. 13C NMR of 3,4-dihydro-8-allyl-3-(4-nitrophenyl)-1,3-2H-benzoxazine, 10

Figure S31. MS (EI) of 3,4-dihydro-8-allyl-3-(4-nitrophenyl)-1,3-2H-benzoxazine, 10

S25

3,4-Dihydro-8-allyl-3-Phenyl-1,3-2H-benzoxazine, 115 (Scheme 1 and Table 1)

Orange liquid (77 mg, 58%); 1H NMR (600 MHz, CDCl3) δ (ppm): 3.33 (d, J = 6.5 Hz, 2H), 4.62 (s, 2H), 5.00-5.04 (m, 2H), 5.37 (s, 2H), 5.93-5.99 (m, 1H), 6 .82 (t, J = 6.8 Hz, 1H), 6.88 (d, J = 6.8 Hz, 1H), 6.92 (td, J = 7.4 Hz, 1.1 Hz, 1H) 6.98 (d, J = 7.0 Hz, 1H) 7.10-7.12 (m, 2H) 7.24-7.27 (m, 2H); 13C NMR (150 MHz, CDCl3) δ (ppm): 33.75 (C-15), 50.74 (C-5), 79.43 (C-6) 115.56 (C-17), 118.34 (C-9, C-13), 120.45 (C-11), 120.51 (C-8), 121.48 (C-3), 124.82 (C-4), 128.19 (C-1), 128.22 (C-2), 129.33 (C-10, C-12), 136.77 (C-16), 148.50 (C-14), 152.12 (C-7). GC-MS (EI), m/z calcd for C17H17NO 251.13 found 251, 145, 131, 115, 105, 77, 65, 51, 39. Rt = 29.967 min

LR148NEW_Proton-1-1.esp


0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

7.27

7.27

7.26 7.

267.

257.

247.

127.

127.

117.

107.

106.

97 6.94

6.87

6.82

6.81

5.99

5.98

5.97 5.

945.

93

5.37

5.04

5.04

5.03

5.01

5.01

5.01

5.00

4.62

3.33

3.32

Figure S32. 1H of 3,4-dihydro-8-allyl-3-phenyl-1,3-2H-benzoxazine, 11

S26

LR148NEW_Carbon-1.esp


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

152.

12

148.

50 136.

77

129.

3312

8.22

124.

8212

1.48

120.

4511

8.34

115.

56

79.4

3

50.7

4

33.7

5

Figure S33. 13 C of 3,4-dihydro-8-allyl-3-phenyl-1,3-2H-benzoxazine, 11

Figure S34. MS (EI) of 3,4-dihydro-8-allyl-3-phenyl-1,3-2H-benzoxazine, 11

S27

3,4-Dihydro-8-allyl-3-benzyl-1,3-2H-benzoxazine, 12 (Scheme 1 and Table 1)

White powder (71 mg, 50%); 1H NMR (600 MHz, CDCl3) δ (ppm): 3.37 (d, J = 6.5 Hz, 2H), 3.92 (s, 2H), 3.99 (s, 2H), 4.9 (s, 2H), 5.06-5.1 (m, 2H), 6.01-6.05 (m, 1H), 6 .81-6.86 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.34-7.38 (m, 5H); 13C NMR (150 MHz, CDCl3) δ (ppm): 33.86 (C-15), 49.97 (C-5), 55.63 (C-9), 82.13 (C-6), 115.54 (C-17), 119.45 (C-8), 120.36 (C-3), 125.79 (C-4), 127.51 (C-13), 127.71 (C-1), 128.18 (C-2), 128.60 (C-14, C-12), 129.22 (C-15, C-11), 136.77 (C-16), 138.08 (C-10), 151.77 (C-7). GC-MS (EI), m/z calcd for C18H19NO 265.1 found 265, 174, 145, 131, 120, 115, 91, 65, 51, 39. Rt = 29.172 min

LR150_Proton-1-1.esp

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

M01(d)

M03(m)

M02(d)

7.38

7.37

7.35

7.34

7.34

7.31

7.31 7.

30 7.04 7.

036.

856.

84 6.82

6.81

6.05

6.04 6.

04 6.02

6.02

6.01 6.01 6.01

5.10

5.10

5.08 5.07

5.07

5.06

4.90

3.99

3.92

3.39

3.37

Figure S35. 1H NMR of 3,4-dihydro-8-allyl-3-benzyl-1,3-2H-benzoxazine, 12

S28

LR150_Carbon-1.asc


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

151.

77

138.

0313

6.94

129.

2212

8.60

128.

1812

5.79

120.

3611

9.45

115.

54

82.1

3

55.6

3

49.9

7

33.8

6

Figure S36. 13C NMR of 3,4-dihydro-8-allyl-3-benzyl-1,3-2H-benzoxazine, 12

Figure S37. MS (EI) of 3,4-dihydro-8-allyl-3-benzyl-1,3-2H-benzoxazine, 12

S29

3,4-Dihydro-3-allyl-3-benzyl-1,3,2H-benzoxazine, 13 (Scheme 1 and Table 1)

Pale yellow oil (90 mg, 45%); 1H NMR (600 MHz, CDCl3) d (ppm): 3.39 (d, J = 6.5 Hz, 2H), 4.00 (s, 2H), 4.87 (s, 2H), 5.19-5.24 (m, 2H), 5.87-5.94 (m, 1H), 6.79 (d, J = 7.9 Hz, 2H), 6.87 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 7.34-7.12 (t, J = 7.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) d (ppm): 49.61 (C-5), 54.60 (C-9), 55.63 (C-9), 82.11 (C-6) ,116.50 (C-1), 118.44 (C-11), 120.08 (C-8), 120.69 (C-3), 127.64 (C-4) 127.77 (C-2), 135.08 (C-10), 154.20 (C-7). GC-MS (EI), m/z calcd for C11H13NO 175.10 found 175, 134, 107, 78, 68, 51, 41, 39. Rt = 20.916 min

LR152_Proton-3-1 (ULTIMO NMR POST STRIPPAGGIO).esp


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Nor

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ized

Inte

nsity

7.25 7.

147.

126.

956.

94 6.87

6.80

6.78

5.93 5.

915.

905.

89

5.24

5.24

5.22 5.21 5.21

5.19

4.87

4.00

3.40

3.39

Figure S38. 1H NMR of 3,4-dihydro-3-allyl-3-benzyl-1,3-2H-benzoxazine, 13

S30

LR152_Carbon-1.esp

220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

154.

20

135.

0812

7.77

127.

6412

0.08

118.

4411

6.50

82.1

1

54.6

049

.61

Figure S39. 13C NMR of 3,4-dihydro-3-allyl-3-benzyl-1,3-2H-benzoxazine, 13

Figure S40. 13C NMR of 3,4-dihydro-3-allyl-3-benzyl-1,3-2H-benzoxazine, 13.

S31

3,4-Dihydro-8-allyl-3-(4-methoxyphenyl)-1,3-2H-benzoxazine, 14 (Scheme 1 and Table 1)

Orange Liquid (55 mg, 37%), 1H NMR (600 MHz, CDCl3) δ (ppm): 3.31 (d, J = 6.5 Hz, 2H, CH2-15), 3.73 (s, 3H, CH3-18), 4.53 (s, 2H, CH2-5), 4.99-5.03 (m, 2H, CH2-17), 5.28 (s, 2H, CH2-6), 5.93-5.98 (m, 1H, CH-16), 6.78-6.81 (m, 3H, CH-3, CH-12, CH-10), 6.85 (d, J = 7 Hz, 1H, CH-4), 6.97 (d, J = 7.4 Hz, 1H, CH-2), 7.06 (d, J = 8.4 Hz, 2H, CH-9, CH-13). 13C NMR (150 MHz, CDCl3)1 δ (ppm): 34.22 (C-15), 50.88 (C-18), 56.06 (C-5), 81.15 (C-6), 115.01 (C-9, C-13) 115.99 (C-17), 120.81 (C-3), 120.95 (C-8), 121.31 (C-12, C-10), 125.30 (C-4), 128.52 (C-1), 128.68 (C-2), 137.31 (C-11), 143.00 (C-16), 152.54 (C-14), 155.47(C-7); GC-MS (EI), m/z calcd for C18H19NO2 281.35 found 281, 145, 135, 120, 92, 65, 39. Rt = 29.96 min.

LR149DSF2_Proton-1-1.jdf


0.05

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0.40

0.45

0.50

0.55

0.60

0.65

0.70

Nor

mal

ized

Inte

nsity

7.24

7.06 7.

056.

976.

976.

816.

806.

806.

78

5.98

5.93

5.28

5.03

5.02 5.02

5.00

5.00 5.00

4.99

4.53

3.73

3.32

3.31

Figure S41. 1H of 3,4-Dihydro-8-allyl-3-(4-methoxyphenyl)-1,3-2H-benzoxazine, 14

S32

LR149DSF2_Carbon-1-1.jdf


0

0.1

0.2

0.3

0.4

0.5

0.6

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0.9

1.0

Nor

mal

ized

Inte

nsity

155.

4815

2.55

143.

00

137.

31

128.

6812

8.52

125.

30

121.

3112

0.81

115.

9911

5.01

81.1

5

56.0

6

51.9

9

34.2

2

Figure S42. 13C of 3,4-Dihydro-8-allyl-3-(4-methoxyphenyl)-1,3-2H-benzoxazine, 14

Figure S43. MS (EI) of 3,4-Dihydro-8-allyl-3-(4-methoxyphenyl)-1,3-2H-benzoxazine, 14

S33

References

1. A. Mascitti, M. Lupacchini, R. Guerra, I. Taydakov, L. Tonucci, N. d’Alessandro, F. Lamaty, J. Martinez and E. Colacino, Beilstein J. Org. Chem., 2017, 13, 19-25.

2. G. P. Moloney, D. J. Craik and M. N. Iskander, Magnetic Res. Chem., 1990, 28, 824-829. 3. D. K. Shukla, M. Rani, A. A. Khan, K. Tiwari and R. K. Gupta, Asian J. Chem., 2013, 25, 5921-

5924. 4. J. Liu and G. Yuan, Tetrahedron Lett., 2017, 58 1470-1473. 5. B. Kiskan and Y. Yagci, J. Polym. Sci., Part A: Pol. Chem., 2014, 52, 2911–2918.

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