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Supporting Information for:

One-Pot Sequential Reaction to 2-Substituted-Phenanthridinones

from N–Methoxybenzamides

Dongdong Liang,a Deanna Sersen,a Chao Yang,c Jeffrey R. Deschamps,b Gregory H.

Imler,b Chao Jiang,c,* and Fengtian Xue.a,*

aDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy,

20 Penn Street, Baltimore, Maryland 21201, United States

bNaval Research Laboratory, Code 6930, 4555 Overlook Ave., Washington, DC

20375, United States

cDepartment of Pharmaceutical Engineering, School of Chemical Engineering,

Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China.

Table of Contents

I. Supplemental Material for Reactions. ................................................................. 2

II. Mechanistic Studies ............................................................................................ 4

1. Control Reaction: .................................................................................. 4

2. NMR Experiment .................................................................................. 7

IV. References: ...................................................................................................... 10

V. Copies of 1H NMR and 13C NMR Spectra .......................................................... 11

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

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I. Supplemental Material for Reactions.

Bromination:

Scheme S1. PIDA was used directly instead of PhI and AcOOHa,b

aReaction conditions: substrate 1 (0.25 mmol), TBAB (1.2 equiv.) iodosobenzene diacetate (PIDA)

(2.5 equiv.) in 1.0 mL HFIP was stirred at room temperature for 3 h. bIsolated yields and the yields

in parentheses were obtained using PhI (20 mol %) and AcOOH (2.5 equiv.) instead of PIDA (2.5

equiv).

Chlorination: To a solution of N-methoxy-[1,1'-biphenyl]- 2-carboxamide (0.25

mmol, 1 equiv) and tetrabutyl ammonium chloride (TBAC) (104 mg, 0.375 mmol, 1.5

equiv) in HFIP (1.0 mL) was added PhI (5.6 μL, 0.05 mmol, 20 mol%) and

peroxyacetic acid (2.5 equiv) (32 wt.% in dilute acetic acid, 131 μL, 0.625 mmol,

2.5.0 equiv) or PIDA (201 mg, 0.625 mmol, 2.5 equiv) at 25 oC under air. The

resulting mixture was stirred at 25 oC for 12 h. The reaction was monitored using TLC

until the starting material was completely consumed. The reaction mixture was diluted

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with EtOAc (20 mL) and washed with brine (20 mL). The organic layer was dried

over Na2SO4, and concentrated under vacuum. The resulting crude product was

purified by column chromatography (hexane/EtOAc) to give the desired products

3a-f.

While for other substrates in addition to 1a with the catalytic conditions, a mixture

of the inseparable chlorinated and unchlorinated phenanthridinones was obtained. See

examples as follows:

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II. Mechanistic Studies

1. Control Reaction:

(1) Standard conditions without PhI:

To a solution of N-methoxybenzamide 1a (71.3 mg, 0.25 mmol,) in HFIP (1 mL) was

added TBAB (97 mg, 0.3 mmol, 1.2 equiv) and AcOOH (tech. ca 32% dilute in

AcOOH, 131 μL, 0.625 mmol, 2.5 equiv) at room temperature under air. The reaction

was stirred for 3 h. no obvious product was been tested which show that PhI is a real

catalyst for this reaction.

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(2) Remove TBAB and reduce the oxidant AcOOH to 1.2 equiv:

To a solution of N-methoxybenzamide 1a (71.3 mg, 0.25 mmol,) in HFIP (1 mL) was

added PhI (0.025 mmol, 2.8 μL, 0.1 equiv) and AcOOH (tech. ca 32% dilute in

AcOOH, 66 μL, 0.30 mmol, 1.2 equiv) at room temperature under air. After stirring

the reaction for an additional 1 h, the solvent was removed under vacuum to afford

compound of 1a’ as a white solid (47 mg, 84%): 1H NMR (400 MHz, CDCl3): δ 8.49

(d, J = 7.6 Hz, 1H), 8.20 (dd, J = 2.0 Hz, J = 8.0 Hz, 2H), 7.71 (t, J = 8.0 Hz, 1H),

7.61 (d, J = 8.4 Hz, 1H), 7.54-7.50 (m, 2H), 7.30-7.26 (m, 1H), 4.07 (s, 3H); 13C

NMR (100 MHz, CDCl3): δ 157.5, 136.0, 133.1, 132.8, 130.1, 128.7, 128.3, 126.5,

123.4, 122.1, 118.7, 112.8, 62.9.

The result shown that maybe 1a’ is the intermediate of this Sequential Reaction.

(3) Reduce the amount of AcOOH to 1.2 equiv:

To a solution of N-methoxybenzamide 1a (71.3 mg, 0.25 mmol,) TBAB (97mg, 0.3

mmol, 1.2 equiv) in HFIP (1 mL) was added PhI (0.05 mmol, 5.6 μL, 0.2 equiv) and

AcOOH (tech. ca 32% dilute in AcOOH, 66 μL, 0.30 mmol, 1.2 equiv) at 25 oC under

air. After stirring the reaction for an additional 4 h, the solvent was removed under

vacuum to afford compound 2a (27 mg, 36%) as a white solid, along with the

recovery of compound 1a (32 mg, 56%). It shown the step of bromination is very fast.

When intermediate emerged, it rapidly transformed to bromination product.

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(4) 1a’ was submitted to our standard reaction conditions:

To a solution of 5-methoxyphenanthridin-6(5H)-one 1a’ (56.3 mg, 0.25 mmol,)

TBAB (97mg, 0.3 mmol, 1.2 equiv) in HFIP (1 mL) was added PhI (0.05 mmol, 5.6

μL, 0.2 equiv) and AcOOH (tech. ca 32% dilute in AcOOH, 131 μL, 0.625 mmol, 2.5

equiv) at 25 oC under air. After stirring the reation mixture at 25 oC for an additional 4

h, the solvent was removed under vacuum to afford compound 2a (57.6 mg, 76%) as a

white solid. It confirmed that 1a’ is an intermediate.

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2. NMR Experiment1

Figure S1. 1: the 1H-NMR spectrum of PhI; 2 the 1H-NMR spectrum of PIDA; 3: Ten

min after mixing PhI, AcOOH and TBAB (0.2:1:1); 4: One hour after mixing PhI,

AcOOH and TBAB (0.2:1:1); 5: Four hours after mixing PhI, AcOOH and TBAB

(0.2:1:1); 6: 24 hours after mixing PhI, AcOOH and TBAB (0.2:1:1).

Form Figure S1, we found that mixing of PhI, AcOOH and TBAB in 30 min,

PIDA appeared. The amount of PIDA peaks at 4 h. This result shown that TBAB was

been oxidized by in situ to generate PIDA.

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Figure S2. 1: the 1H-NMR spectrum of PhI; 2 the 1H-NMR spectrum of PIDA; 3: Ten

min after mixing PhI, AcOOH and TBAB (1:1:1); 4: One hour after mixing PhI,

AcOOH and TBAB (1:1:1); 5: Four hours after mixing PhI, AcOOH and TBAB

(1:1:1); 6: 24 hours after mixing PhI, AcOOH and TBAB (1:1:1).

When the ratio of PhI:AcOOH:TBAB was 1:1:1, similar NMR results were obtained

as Figure S1.

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Figure S3. 1: the 1H-NMR spectrum of PhI; 2 the 1H-NMR spectrum of PIDA; 3: Ten

min after mixing PIDA and TBAB (1:1); 4: One hour after mixing PIDA and TBAB

(1:1); 3: Four hours after mixing PIDA and TBAB (1:1); 3: 24 hours after mixing

PIDA and TBAB (1:1).

Figure S3 shown that treatment of iodosobenzene diacetate with TBAB leads to the

reduction of iodosobenzene diacetate to iodobenzene.

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IV. References:

(1) P. A. Evans, T. A. Brandt, J. Org. Chem. 1997, 62, 5321.

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V. Copies of 1H NMR and 13C NMR Spectra

Compound 2a

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Compound 2b

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Compound 2c

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Compound 2d

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Compound 2e

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Compound 2f

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Compound 2g

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Compound 2h

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Compound 2i

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Compound 2j

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Compound 2k

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Compound 2l

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Compound 2m

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Compound 2n

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Compound 3a

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Compound 3b

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Compound 3c

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Compound 3d

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Compound 3e

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Compound 3f

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Compound 4

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Compound 5

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Compound 6

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Compound 7

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Compound 8

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Compound 10

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Compound 12

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