supporting information - royal society of chemistry · 3 general procedure of n-alkylation of...

1

Supporting Information

Fine-tuning the regio- and chemoselective alkylation of 1,4-benzodiazepines:

Further applications of the Mitsunobu reaction

Kwan-Young Junga and Steven Fletcher*

a,b

aDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine St.,

Baltimore, MD 21201, USA. E-mail: [email protected]; Fax: +1-410-706-5017; Tel: +1-

410-706-6361

bUniversity of Maryland Marlene and Stewart Greenebaum Cancer Center, 22 S Greene St, Baltimore,

MD 21201, USA

General.

Unless otherwise stated, all reactions were performed under an inert (N2) atmosphere. Reagents and

solvents were reagent grade and purchased from Sigma-Aldrich, Alfa Aesar, Oakwood and TCI

America. 1H and

13C NMR spectra were recorded on Varian INOVA 400 MHz and Varian INOVA 500

MHz NMR spectrometers at 25 °C. Chemical shifts are reported in parts per million (ppm). The

residual solvent peak was used as an internal reference. The mass spectra were obtained on an

Electrospray TOF (ESI-TOF) mass spectrometer (Bruker amaZon X). IR spectra were recorded on an

FT-IR 400 spectrometer (JASCO). Melting points were obtained using a MEL-TEMP II (Laboratory

Devices, Inc. USA).

Abbreviations.

EtOAc, ethyl acetate; MeOH, methanol; DMSO, dimethyl sulfoxide; DMF, N,N-dimethylformamide;

THF, tetrahydrofuran; Et2O, diethyl ether; CH3CN, acetonitrile; CH2Cl2, dichloromethane; CHCl3,

chloroform; HNEt2, diethylamine; IBCF, isobutyl chloroformate; NMM, N-methylmorpholine; NH4Cl,

ammonium chloride; Na2SO4, sodium sulfate; K2CO3, potassium carbonate; NaHCO3, sodium

bicarbonate; DIAD, diisopropyl azodicarboxylate; PBu3, tributylphosphine; PPh3, triphenylphosphine;

PMe3, trimethylphosphine; PCy3, tricyclohexylphosphine; SOCl2, thionyl chloride; (COCl)2, oxalyl

chloride; DIPEA, N,N-diisopropylethylamine; NaBH(OAc)3, sodium triacetoxyborohydride; p-TsOH,

para-toluenesulfonic acid; Bu4NI, tetrabutylammonium iodide; Na2SO4∙10H2O, sodium sulfate

decahydrate; s, singlet; d, doublet; t, triplet; q, quartet; pent, pentet; sep, septet; dd, doublet of

doublets; dt, doublet of triplets; dq, doublet of quartets.

Electronic Supplementary Material (ESI) for Medicinal Chemistry CommunicationsThis journal is © The Royal Society of Chemistry 2012

2

Experimental Section.

Aspartic acid dimethyl ester∙HCl (6). Aspartic acid 5 (3.0 g, 22.5 mmol) was dissolved in methanol

(110 mL) and cooled to 0 °C. Thionyl chloride (4.9 mL, 67.6 mmol) was added dropwise at 0 °C and

the reaction mixture was stirred for 3 h at 50 °C. The reaction solvent and thionyl chloride were

removed by evaporation under reduced pressure to give the product 6 as white solid (4.43 g, 100%):

1H NMR (500 MHz, DMSO-d6) δ 8.74 (2H, s, NH2∙HCl), 4.35 (1H, m, CHNH2), 3.76 (3H, s, OCH3),

3.65 (3H, s, OCH3), 3.02 (2H, m, CH2).

(S)-Methyl 2-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl)acetate (1). Aspartic

acid dimethyl ester∙HCl 6 (1.53 g, 9.38 mmol) and isatoic anhydride (1.85 g, 9.38 mmol) were

dissolved in pyridine (20 mL) then the reaction mixture was stirred for 24 h at 120 °C. The pyridine

was removed by evaporation under reduced pressure and the residue was re-dissolved in ethyl acetate

then partitioned between ethyl acetate and 1N HCl aqueous solution. The organic layer was collected,

dried over anhydrous Na2SO4, filtered, and concentrated. The light brown solid was washed with

water (3 x 10 mL) and diethyl ether (3 x 10 mL) to give product 1 as light brown solid (1.05 g, 45.0%):

Mp 230-232 °C; 1H NMR (500 MHz, DMSO-d6) δ 10.48 (1H, s, NH), 8.59 (1H, d, J=4.5 Hz, NH),

7.76 (1H, d, J=8.0 Hz, phenyl), 7.54 (1H, t, J=8.0 Hz, phenyl), 7.26 (1H, t, J=8.0 Hz, phenyl), 7.13

(1H, d, J=8.0 Hz, phenyl), 4.04 (1H, m, CHCH2), 3.58 (3H, s, OCH3), 2.88 (1H, dd, J=8.0 Hz, 8.5 Hz,

CHCH2), 2.73 (1H, dd, J=6.0 Hz, 6.5 Hz, CHCH2); 13

C NMR (125 MHz, DMSO-d6) δ 170.7, 170.5,

167.6, 136.5, 132.3, 130.4, 126.1, 124.2, 121.0, 51.5, 48.5, 32.4; I.R. (neat): ν/cm-1

3102, 3023, 1735,

1681, 1656, 1446, 1269, 1183, 756; MS (ESI) m/z Calcd for C12H12N2O4+H (M+H+): 249.0, Found:

249.1.


3

General procedure of N-alkylation of compound 1 using potassium carbonate.

Compound 1 (50 mg, 0.20 mmol) and K2CO3 (83 mg, 0.60 mmol) were added to the reaction flask

containing 4 mL of DMF. The reaction mixture was stirred at room temperature for 20 min then 2-

iodopropane (50 µL, 0.50 mmol) or benzyl bromide (120 µL, 0.50 mmol) was added. The reaction

mixture was stirred at 60 °C (2-iodopropane) or at room temperature (benzyl bromide) overnight. The

reaction was quenched by adding H2O (4 mL), then partitioned between EtOAc and sat’d NH4Cl (aq).

The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated, and purified by

column chromatography on silica gel to give the compound N-2c (R=benzyl) or N-2e (R-isopropyl).

(S)-methyl 2-(1-benzyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-

benzo[e][1,4]diazepin-3-yl)acetate (N-2c). Yield = 45.6 mg, 67.0%;

White solid; Mp 73-74 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.81 (1H, d,

J=6.0 Hz, NH), 7.67 (1H, d, J=8.0 Hz, phenyl), 7.56 (1H, t, J=7.5 Hz,

phenyl), 7.47 (1H, d, J=7.5 Hz, phenyl), 7.32 (1H, t, J=8.0 Hz, phenyl),

7.25 (2H, t, J=8.0 Hz, phenyl), 7.19 (1H, t, J=7.5 Hz, phenyl), 7.09 (2H, d,

J=7.5 Hz, phenyl), 5.24 (1H, d, J=15.5 Hz, CH2C6H5), 5.05 (1H, d, J=15.5 Hz, CH2C6H5), 4.20-4.16

(1H, m, CHCH2), 3.59 (3H, s, OCH3), 2.97 (1H, dd, J=10.0 Hz, J=8.5 Hz, CHCH2), 2.79 (1H, dd,

J=5.5 Hz, J=5.5 Hz, CHCH2); 13

C NMR (125 MHz, DMSO-d6) δ 170.5, 169.7, 167.3, 139.1, 137.1,

132.2, 129.7, 129.5, 128.4, 127.0, 126.6, 125.9, 122.3, 51.6, 49.8, 48.8, 32.7; I.R. (neat): ν/cm-1

3108,

1662, 1601, 1460, 1399, 1252, 1185, 764, 731, 698; MS (ESI) m/z Calcd for C19H18N2O4+H (M+H+):

339.1, Found: 339.2.

(S)-methyl 2-(1-isopropyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-

benzo[e][1,4]diazepin-3-yl)acetate (N-2e) Yield = 11.1 mg, 19.0 %;

White solid; Mp 146-148 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.68 (1H,

d, J=4.8 Hz, NH), 7.68 (1H, d, J=8.0 Hz, phenyl), 7.62 (1H, t, J=8.0 Hz,



4

4.36 (1H, sep, J=7.0 Hz, CH(CH3)2), 3.96 (1H, q, J=6.0 Hz, CHCH2), 3.56 (3H, s, OCH3), 2.89 (1H,

dd, J=8.5 Hz, J=8.0 Hz, CHCH2-1H), 2.69 (1H, dd, J=6.0 Hz, J=6.0 Hz, CHCH2), 1.39 (3H, d, J=6.5

Hz, CH3), 1.18 (3H, d, J=7.0 Hz, CH3); 13

C NMR (125 MHz, DMSO-d6) δ 170.6, 169.5, 167.4, 138.8,

131.8, 130.4, 129.1, 126.4, 124.1, 52.0, 51.5, 49.7, 32.5, 21.3, 20.1; I.R. (neat): ν/cm-1

3202, 1655,

1641, 1598, 1458, 1368, 1196, 1154, 771; MS (ESI) m/z Calcd for C15H18N2O4+H (M+H+): 291.1,

Found: 291.1.

General procedure of N- or O-alkylation of compound 1 using Mitsunobu reaction.

Compound 1 (40 mg, 0.16 mmol), the appropriate alcohol (0.40 mmol), and triphenylphosphine (99

µL, 0.40 mmol) were added to the reaction flask containing 5 mL of THF under an inert (N2)

atmosphere. The reaction mixture was stirred for 5 min. at room temperature and then DIAD (79 µL,

0.40 mmol) was added slowly. The reaction mixture was then stirred for 4 h at room temperature. The

reaction solvent was removed by evaporation under reduced pressure and the residue was purified by

column chromatography on silica gel (hexanes–EtOAc, 1:9) to afford product.

(S)-Methyl 2-(2,5-dioxo-1-(prop-2-yn-1-yl)-2,3,4,5-tetrahydro-1H-

benzo[e][1,4]diazepin-3-yl)acetate (N-2a). Yield = 42.9 mg, 93.0%;


J=5.0 Hz, NH), 7.73 (1H, d, J=6.5 Hz, phenyl), 7.69-7.63 (2H, m, phenyl),

7.40 (1H, t, J=7.0 Hz, phenyl), 4.74 (1H, d, J= 18.5 Hz, CH2C≡CH), 4.64

(1H, d, J=18.5 Hz, CH2C≡CH), 4.09-4.05 (1H, m, CH(CH3)2), 3.57 (3H, s, OCH3), 3.19 (1H, s,

CH2C≡CH), 2.94 (1H, dd, J= 9.0 Hz, 7.5 Hz, CHCH2), 2.76 (1H, dd, J=5.5 Hz, 5.0 Hz, CHCH2); 13

C

NMR (125 MHz, DMSO-d6) δ 170.4, 169.1, 167.2, 138.5, 132.3, 129.7, 129.2, 126.2, 122.2, 79.3,

74.8, 51.6, 48.7, 36.4, 32.6; I.R. (neat): ν/cm-1

3302, 3015, 1735, 1661, 1602, 1460, 1374, 1249, 1192,

765; MS (ESI) m/z Calcd for C15H14N2O4+H (M+H+): 287.1, Found: 287.0.

(S)-Methyl 2-(1-allyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-

benzo[e][1,4]diazepin-3-yl)acetate (N-2b). Yield = 43.8 mg, 94.3%;



5

J=5.0 Hz, NH), 7.71 (1H, d, J=7.0 Hz, phenyl), 7.61 (1H, t, J=8.0 Hz, phenyl), 7.48 (1H, d, J=8.0 Hz,

phenyl), 7.36 (1H, t, J=8.0 Hz, phenyl), 5.78-5.72 (1H, m, CH2CH=CH2), 5.08 (2H, d, J=10.5 Hz,

CH2CH=CH2), 4.52 (2H, dd, J=16.5 Hz, 16.5 Hz, CH2CH=CH2), 4.12-4.10 (1H, m, CH(CH3)2), 3.57

(3H, s, OCH3), 2.92 (1H, dd, J=8.5 Hz, 8.5 Hz, CHCH2), 2.75 (1H, dd, J=4.5 Hz, 2.0 Hz, CHCH2);

13C NMR (125 MHz, DMSO-d6) δ 170.5, 169.2, 167.4, 139.3, 133.1, 132.3, 129.6, 129.3, 125.8,

122.2, 116.4, 51.5, 49.4, 48.8, 32.7; I.R. (neat): ν/cm-1

3310, 2200, 1706, 1660, 1602, 1460, 1399,

1375, 1193, 765; MS (ESI) m/z Calcd for C15H16N2O4+H (M+H+): 289.1, Found: 289.0.

(S)-Methyl 2-(1-benzyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-

benzo[e][1,4]diazepin-3-yl)acetate (N-2c). Yield = 41.6 mg, 76.3%;




7.25 (2H, t, J=8.0 Hz, phenyl), 7.19 (1H, t, J=7.5 Hz, phenyl), 7.10 (2H, d,

J=8.5 Hz, phenyl), 5.26 (1H, d, J=16.5 Hz, CH2C6H5), 5.04 (1H, d, J=16.5 Hz, CH2C6H5), 4.21-4.17

(1H, m, CHCH2), 3.59 (3H, s, OCH3), 2.97 (1H, dd, J=8.5 Hz, J=8.5 Hz, CHCH2), 2.79 (1H, dd,

J=5.5 Hz, J=4.5 Hz, CHCH2); 1H NMR (400 MHz, CDCl3) δ 7.84 (1H, d, J=8.0 Hz, phenyl), 7.44

(1H, t, J=8.0 Hz, phenyl), 7.30-7.21 (5H, m, phenyl), 7.14 (1H, t, J=8.0 Hz, phenyl), 6.81 (1H, d,

J=5.6 Hz, NH), 5.16 (1H, d, J=15.6 Hz, CH2C6H5), 5.00 (1H, d, J=15.6 Hz, CH2C6H5), 4.38-4.35 (1H,

m, CHCH2), 3.71 (3H, s, OCH3), 3.06 (1H, dd, J=8.0 Hz, J=8.0 Hz, CHCH2), 2.77 (1H, dd, J=5.6 Hz,

J=5.2 Hz, CHCH2); 13

C NMR (125 MHz, DMSO-d6) δ 170.5, 169.7, 167.3, 139.1, 137.1, 132.2, 129.7,

129.5, 128.4, 127.0, 126.6, 125.9, 122.3, 51.6, 49.8, 48.8, 32.7; I.R. (neat): ν/cm-1

3108, 1662, 1601,


Found: 339.2.

(S)-Methyl 2-(2-(benzyloxy)-5-oxo-4,5-dihydro-3H-

benzo[e][1,4]diazepin-3-yl)acetate (O-2c). Yield = 7.6 mg, 14.0%;

Colorless sticky oil; 1H NMR (500 MHz, DMSO-d6) δ 8.64 (1H, d, J=5.0

Hz, NH), 7.78 (1H, d, J=7.5 Hz, phenyl), 7.55 (1H, t, J=8.0 Hz, phenyl),

7.40-7.35 (5H, m, phenyl), 7.26 (1H, t, J=7.5 Hz, phenyl), 7.18 (1H, d,

J=8.5 Hz, phenyl), 5.36 (1H, d, J=13.0 Hz, CH2C6H5), 5.24 (1H, d, J=13.0

Hz, CH2C6H5), 4.09 (1H, q, J=7.0 Hz, CHCH2), 3.54 (3H, s, OCH3), 2.92 (1H, dd, J=9.0 Hz, J=8.5 Hz,

CHCH2), 2.83 (1H, dd, J=7.0 Hz, J=6.0 Hz, CHCH2); 13

C NMR (125 MHz, DMSO-d6) δ 170.3, 169.5,

161.6, 144.3, 135.6, 132.4, 130.4, 128.5, 128.4, 128.2, 128.1, 126.4, 124.5, 69.2, 52.0, 47.5, 32.9; I.R.

(neat): ν/cm-1

2989, 1739, 1654, 1308, 1254, 1153, 766, 730, 697; MS (ESI) m/z Calcd for


6

C19H18N2O4+H (M+H+): 339.1, Found: 339.1.

(S)-Methyl 2-(1-butyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-

benzo[e][1,4]diazepin-3-yl)acetate (N-2d). Yield = 29.6 mg, 60.3%;




4.25 (1H, pent, J=7.0 Hz, CH2CH2CH2CH3), 4.02 (1H, q, J=6.0 Hz,

CHCH2), 3.65 (1H, pent, J=7.0 Hz, CH2CH2CH2CH3), 3.56 (3H, s, OCH3), 2.90 (1H, dd, J=9.0 Hz,

J=9.0 Hz, CHCH2), 2.72 (1H, dd, J=6.0 Hz, J=6.0 Hz, CHCH2), 1.33 (1H, m, CH2CH2CH2CH3), 1.26

(1H, m, CH2CH2CH2CH3), 1.10 (2H, m, CH2CH2CH2CH3), 0.76 (3H, t, J=7.0 Hz, CH2CH2CH2CH3);

13C NMR (125 MHz, DMSO-d6) δ 170.6, 169.4, 167.4, 138.8, 132.3, 129.9, 129.5, 125.9, 122.9, 51.5,

48.9, 45.7, 32.6, 29.2, 18.9, 13.4; I.R. (neat): ν/cm-1

3002, 1738, 1661, 1601, 1460, 1402, 1373, 1193,

790, 767; MS (ESI) m/z Calcd for C16H20N2O4+H (M+H+): 305.1, Found: 305.1.

(S)-Methyl 2-(2-butoxy-5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepin-

3-yl)acetate (O-2d). Yield = 17.2 mg, 35.1%; Colorless sticky oil; 1H

NMR (500 MHz, DMSO-d6) δ 8.61 (1H, s, NH), 7.76 (1H, d, J=7.0 Hz,

phenyl), 7.52 (1H, t, J=7.5 Hz, phenyl), 7.23 (1H, t, J=7.5 Hz, phenyl),

7.13 (1H, d, J=7.5 Hz, phenyl), 4.27 (1H, pent, J=6.5 Hz,

CH2CH2CH2CH3), 4.14 (1H, pent, J=6.5 Hz, CH2CH2CH2CH3), 4.01 (1H,

q, J=5.5 Hz, CHCH2), 3.59 (3H, s, OCH3), 2.88 (1H, dd, J=9.5 Hz, J=8.5 Hz, CHCH2), 2.81 (1H, dd,

J=6.0 Hz, J=6.0 Hz, CHCH2), 1.63 (2H, m, CH2CH2CH2CH3), 1.38 (2H, m, CH2CH2CH2CH3), 0.91

(3H, t, J=7.5 Hz, CH2CH2CH2CH3); 13

C NMR (125 MHz, DMSO-d6) δ 170.3, 167.7, 163.3, 144.1,

131.8, 129.8, 126.8, 125.8, 124.0, 66.4, 51.6, 46.8, 32.3, 29.9, 18.5, 13.6; I.R. (neat): ν/cm-1

2924,


Found: 305.1.

(S)-Methyl 2-(1-isopropyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-

benzo[e][1,4]diazepin-3-yl)acetate (N-2e). Yield = 13.7 mg, 29.2%;

White solid; Mp 145-148 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.68 (1H,

d, J=4.8 Hz, NH), 7.68 (1H, d, J=8.0 Hz, phenyl), 7.62 (1H, t, J=8.0 Hz,


4.36 (1H, sep, J=7.0 Hz, CH(CH3)2), 3.96 (1H, q, J=6.0 Hz, CHCH2), 3.56 (3H, s, OCH3), 2.89 (1H,

dd, J=8.5 Hz, J=8.0 Hz, CHCH2), 2.69 (1H, dd, J=6.0 Hz, J=6.0 Hz, CHCH2), 1.39 (3H, d, J=6.5 Hz,


7

CH3), 1.18 (3H, d, J=7.0 Hz, CH3); 13

C NMR (125 MHz, DMSO-d6) δ 170.6, 169.5, 167.4, 138.8,

131.8, 130.4, 129.1, 126.4, 124.0, 52.0, 51.5, 49.7, 32.5, 21.3, 20.0; I.R. (neat): ν/cm-1

3202, 1655,


Found: 291.1.

(S)-Methyl 2-(2-isopropoxy-5-oxo-4,5-dihydro-3H-

benzo[e][1,4]diazepin-3-yl)acetate (O-2e). Yield = 21.6 mg, 46.1%;

Colorless sticky oil; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (1H, d, J=4.8

Hz, NH), 7.72 (1H, d, J=7.6 Hz, phenyl), 7.48 (1H, t, J=7.2 Hz, phenyl),

7.18 (1H, t, J=7.2 Hz, phenyl), 7.09 (1H, d, J=8.0 Hz, phenyl), 5.12 (1H,

sep, J=5.6 Hz, CH(CH3)2), 3.93 (1H, q, J=7.2 Hz, CHCH2), 3.56 (3H, s, OCH3), 2.84-2.74 (2H, m,

CHCH2), 1.22 (3H, d, J=6.4 Hz, CH3), 1.18 (3H, d, J=6.4 Hz, CH3); 13

C NMR (125 MHz, DMSO-d6)

δ 170.3, 167.7, 162.5, 144.2, 131.8, 129.8, 126.8, 125.8, 123.9, 69.4, 51.6, 46.9, 32.3, 21.1, 21.0; I.R.

(neat): ν/cm-1

3012, 1741, 1650, 1601, 1372, 1309, 1106, 994, 765; MS (ESI) m/z Calcd for

C15H18N2O4+H (M+H+): 291.1, Found: 291.1.

2-(2-(9H-fluoren-9-yl)acetamido)-N-(2-acetylphenyl)acetamide (9). To a cooled solution of Fmoc -

glycine 8 (2.75 g, 9.26 mmol) in THF was added N-methylmorpholine (NMM, 1.57 mL, 12.04 mmol)

and isobutyl chloroformate (IBCF, 1.32 mL, 12.04 mmol) at 0 °C then the reaction mixture was

stirred for 20 min. 2′-Aminoacetophenone 7 (1.01 mL, 8.33 mmol) was added and the reaction

mixture was refluxed for 4 h. The reaction solvent was removed under reduced pressure, and the

residue was partitioned between water (50 mL) and EtOAc (3 x 40 mL). The organic layers were

collected, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue

was purified by column chromatography on silica gel (hexanes–EtOAc, 2:1) to afford compound 9 as

white solid (2.65 g, 76.9%): 1H NMR (400 MHz, DMSO-d6) δ 11.93 (1H, s, NH), 8.56 (1H, d, J=8.8

Hz, phenyl), 8.11 (1H, s, NH), 8.07 (1H, d, J=7.6 Hz, phenyl), 7.92 (2H, d, J=7.2 Hz, Fmoc), 7.79

(2H, d, J=6.8 Hz, Fmoc), 7.64 (1H, t, J=6.8 Hz, phenyl), 7.44 (2H, t, J=6.8 Hz, Fmoc), 7.35 (2H, t,

J=7.2 Hz, Fmoc), 7.24 (1H, t, J=7.6 Hz, phenyl), 4.38 (2H, d, J=6.0 Hz, CH2-Fmoc), 4.32 (1H, m,

Fmoc), 3.82 (2H, d, J=4.8 Hz, C(O)CH2), 2.63 (3H, s, C(O)CH3); 13

C NMR (100 MHz, DMSO-d6) δ

202.7, 169.2, 156.8, 143.8, 140.7, 139.7, 134.6, 132.2, 127.6, 127.0, 125.3, 122.9, 122.8, 120.7, 119.8,

66.1, 66.1, 46.6, 45.3, 28.7.


8

5-Methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (3). Compound 9 (2.58 g, 6.23 mmol) was dissolved

in 20% diethylamine solution in CH3CN and the reaction mixture was stirred for 1 h at room

temperature. The reaction solvent and diethylamine were removed under reduced pressure. The

residue was purified by column chromatography on silica gel (hexanes–EtOAc, 1:3) to afford

compound 3 as white solid (0.94 g, 86.4%): Mp 178-181 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.41

(1H, s, NH), 7.71 (1H, d, J=7.6 Hz, phenyl), 7.49 (1H, t, J=6.8 Hz, phenyl), 7.20 (1H, t, J=6.8 Hz,

phenyl), 7.14 (1H, d, J=7.6 Hz, phenyl), 3.87 (2H, s, CH2), 2.40 (3H, s, CH3); 13

C NMR (100 MHz,

DMSO-d6) δ170.2, 168.9, 137.6, 131.0, 128.6, 128.0, 123.2, 120.9, 56.1, 25.6; I.R. (neat): ν/cm-1

3014,

1737, 1658, 1601, 1461, 1374, 1194, 768; MS (ESI) m/z Calcd for C10H10N2O+H (M+H+): 175.1,

Found: 175.0.

General procedure of Mitsunobu reaction using compound 3

Compound 3 (150 mg, 0.86 mmol), appropriate alcohol (2.15 mmol), and tributylphosphine (530 µL,

2.15 mmol) were added to the reaction flask containing 10 mL of chloroform in N2(g) atmosphere.

The reaction mixture was stirred for 5 min at room temperature and then DIAD (423 μL, 2.15 mmol)

was added slowly. The reaction mixture was stirred for 4 h at room temperature. The reaction solvent

was removed by evaporation under reduced pressure and the residue was purified by column

chromatography on silica gel (hexanes–EtOAc, 1:9) to afford the product.

1-Benzyl-5-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (4a). Yield = 175.5 mg,

77.3%; White solid; Mp 119-122 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.61 (1H, dd,

J=6.8 Hz, 0.8 Hz, phenyl), 7.46-7.41 (2H, m, phenyl), 7.23-7.17 (3H, m, phenyl),

7.13 (1H, t, J=7.2 Hz, phenyl), 6.97 (2H, d, J=7.6 Hz, phenyl), 5.28 (1H, d, J=15.6

Hz, CH2C6H5), 4.91 (1H, d, J=15.6 Hz, CH2C6H5), 4.32 (1H, d, J=10.8 Hz, NCH2),

3.61 (1H, d, J=10.8 Hz, NCH2), 2.31 (3H, s, CH3); 13

C NMR (100 MHz, DMSO-d6)

δ 169.6, 168.9, 140.5, 137.6, 131.4, 131.3, 128.8, 128.0, 127.4, 127.0, 125.2, 122.6, 56.2, 49.2, 25.4;

I.R. (neat): ν/cm-1

3110, 1738, 1656, 1376, 1228, 778; MS (ESI) m/z Calcd for C17H16N2O+H (M+H+):

265.1, Found: 265.1.


9

1-Isopropyl-5-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (4b). Yield = 63.5 mg,

34.2%; Colorless oil; 1H NMR (400 MHz, DMSO-d6) δ 7.64 (1H, dd, J=6.4 Hz, 1.2

Hz, phenyl), 7.51 (1H, dt, J=5.6 Hz, 1.6 Hz, phenyl), 7.40 (1H, dd, J=5.6 Hz, 0.8 Hz,

phenyl), 7.29 (1h, dt, J=6.4 Hz, 1.2 Hz, phenyl), 4.25 (1H, sep, J=6.8 Hz, CH(CH3)2),

4.13 (1H, d, J=10.8 Hz, NCH2), 3.40 (1H, d, J=10.8 Hz, NCH2), 2.36 (3H, s, CH3), 1.32 (3H, d, J=6.8

Hz, CH3), 1.17 (3H, d, J=6.8 Hz, CH3); 13

C NMR (100 MHz, DMSO-d6) δ 169.4, 169.1, 140.6, 131.8,

130.9, 127.7, 125.6, 123.8, 57.3, 51.6, 25.3, 21.8, 20.4; I.R. (neat): ν/cm-1

3001, 1670, 1630, 1447,

1322, 1250, 756; MS (ESI) m/z Calcd for C13H16N2O+H (M+H+): 217.1, Found: 217.1.

Experimental detail for Mitsunobu reaction using triphenylphosphine resin.

A mixture of compound 1 (15.0 mg, 0.06 mmol), triphenylphosphine resin (“PS-PPh3”; loading

capacity: 2.09 mmol/g, 86 mg, 0.18 mmol) and benzyl alcohol (19 µL, 0.18 mmol) or isopropanol (14

µL, 0.18 mmol) in CHCl3 (2 mL) was gently stirred for 5 min at room temperature. DIAD (36 µL,

0.18 mmol) was added and the reaction mixtures were stirred at room temperature (benzyl alcohol) or

40 °C (isopropanol). The reactions were monitored by thin layer chromatography. The benzyl alcohol

reaction was complete within 3 h, whilst the isopropanol reaction was left overnight to ensure all of 1

was consumed. The NMR spectral data for the major products obtained in the benzyl alcohol and

isopropanol reactions were consistent with those for N-2c and N-2e obtained in the respective solution

phase Mitsunobu reactions.


10


11


12


13


14


15


16


17


18


19


20


21


22


23


24


supporting information - royal society of chemistry · 3 general procedure of n-alkylation of...

Documents