n-mannich bases of aromatic heterocyclic amides: synthesis

S1

Supporting Information

N-Mannich bases of aromatic heterocyclic amides: Synthesis via copper catalyzed

aerobic cross-dehydrogenative coupling under ambient conditions

Shailendra K. Singh,# Nisha Chandna,

# and Nidhi Jain*

Department of Chemistry, Indian Institute of Technology, New Delhi-110016

*E-mail: [email protected]; Fax: +91 11 26581102; Tel: +91 11 26591562

#equal contribution

Table of content

S.N. Particulars Pages

1. Figure S1, Proposed Mechanism, Figure S2

S2

2. Experimental

S3

3. General Procedure for the preparation of N, N-dimethyl aryl amines S4

4. General procedure for the synthesis of compounds (3a-3h, 4a-4c, 6a-6e,

8a-8k and 10a-10f)

S4

5. Procedure for free radical reaction: Inhibition by TEMPO

S4-S5

6.

Procedure for the synthesis of N-trideuteromethyl-N-methyl aniline from

N-methylaniline

S5

7. Reaction with deuterated analogs to study kH/kD

S5-S6

8.

Procedure for oxidation of 4-chloro-N,N-dimethylaniline with air in the

presence of CuBr

S6

9. Spectral data:

1H NMR,

13C{1H} NMR, and HRMS

S7-S18

10. Crystallographic Description

S19-S20

11. References

S21

12. Spectra:

1H NMR,

13C{1H} NMR

S22-S54

13. Spectra of Mechanistic Studies

S55-S56

14. LC-MS spectra of kH/kD experiment S57-S58

mailto:[email protected]

S2

Figure S1. Examples of pharmacologically potent N-Mannich bases of isatin and phthalimide

Proposed Mechanism

The proposed mechanism is given in Figure S2. We believe that the reaction proceeds by an

initial one electron oxidation in presence of copper(I) and oxygen to give an aminium cation

radical. This is followed by loss of proton to yield α-amino radical A. Subsequent electron loss

from A results in the formation of an iminium ion-copper hydroxo intermediate B.1

Nucleophilic

attack by amide on B results in the C-N bond formation yielding the coupled product along with

removal of water molecule. Additionally, A may be interfered by the available oxygen which

promotes a side reaction, resulting in the formation of monomethyl amine 1’ (always formed as a

trace product) through an intermediate C. This pathway also explains the formation of 1b’ and

13 in the control experiment (Scheme 7(3)).2, 3

Figure S2. Proposed Mechanism

S3

EXPERIMENTAL:

General Information:

All reactions were carried out under an air atmosphere in oven-dried round bottom flasks.

Reagents were purchased at the highest commercial quality and used without further purification,

unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried

out on a 0.25 mm silica gel plates (60F254) and visualized under UV illumination at 254 nm

and iodine chamber. Further visualization was achieved by iodine vapour adsorbed on silica gel

depending on the product type. Organic extracts were dried over anhydrous sodium sulphate.

Solvents were removed in a rotary evaporator under reduced pressure. Column chromatography

was performed on silica gel 100200 mesh using a mixture of hexane and ethyl acetate as eluent,

an isolated compounds were characterized by 1H NMR,

13C{1H} NMR, and HRMS data. NMR

spectra for all the samples were taken in deuterochloroform (CDCl3) and dimethylsufoxide-d6

(DMSO-d6) as the solvents. 1H and

13C-NMR spectra were recorded at ambient temperature on

400MHz/300 MHz and 75 MHz spectrometer using tetramethylsilane (TMS) as internal

reference. The chemical shifts are quoted in δ units, parts per million (ppm) up field from the

signal of internal TMS. 1H NMR data is represented as follows: Chemical shift, multiplicity (s =

singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet), integration and

coupling constant(s) J in Hertz (Hz). High resolution mass spectra (HRMS) were recorded on a

Mass spectrometer using electrospray ionization-time of flight (ESI-TOF) reflectron

experiments.

Reagent Information:

All reagents were weighed and handled in air at room temperature. All the solvents were bought

from Aldrich, Spectrochem and were used as received. Copper (I) bromide was purchased from

Alfa-Aesar (98% purity). For column chromatography, silica gel (100–200 mesh), and (230-400)

from SRL Co. was used. A gradient elution using ethyl acetate-hexane was performed, based on

Merck aluminium TLC sheets (silica gel 60F 254). Various amides and N-heterocycles were

bought from Spectrochem, Sigma Aldrich; and anilines were bought from Spectrochem, and

Merck. Trimethylphosphate was bought from Spectrochem Aldrich.

S4

General Procedure for the preparation of N, N-dimethyl aryl amines

A mixture of trimethyl phosphate (8.4 g, 60 mmol) and aniline (40 mmol) was stirred at 110 °C

for 2 h and then cooled to room temperature. The solution was neutralized with 25 mL NaOH

(20%) and stirred at 110 °C for another 12 h. After the reaction, water was added to dissolve the

resultant Na3PO4 and the organic layer was collected. The aqueous phase was extracted with

diethyl ether (3 × 50 mL) and the combined organic phase was dried over anhydrous sodium

sulfate. Removal of solvent under reduced pressure afforded crude N,N-dimethylarylamines,

which were further purified on a silica gel column to give the corresponding N,N-

dimethylarylamines 1. Synthesized compounds were confirmed by 1H NMR, and

13C NMR

spectral data.

General procedure for the synthesis of compounds (3a-3h, 4a-4c, 6a-6e, 8a-8k and 10a-10f):

An oven-dried microwave tube was charged with magnetic stirrer, N-substituted aniline

(1) (1 mmol), oxindole (2)/alkylidene derivative of oxindole (2’)/isatin (5)/phthalimide

(7)/simple and cyclic amides (9) (1 mmol) in acetonitrile as the solvent. To it, CuBr (10 mol%)

was added, and the contents were stirred at room temperature for 12 h in presence of air. The

mixture was diluted with ethyl acetate (3 X 10 mL), the combined organic layer was dried over

anhydrous Na2SO4 and concentrated over vacuum. The residue was purified over a column of

silica gel using ethyl acetate-hexane as the eluent to give the desired product. Synthesized

compounds were confirmed by 1H NMR,

13C NMR and HRMS data.

Procedure for free radical reaction: Inhibition by TEMPO

An oven-dried microwave tube was charged with magnetic stirrer, N,N-dimethyl-p-

toluidine (1a) (1 mmol), oxindole (2)/phthalimide (7) (1 mmol) in acetonitrile as the solvent. To

it, CuBr (10 mol%) and TEMPO (1, 2, 3, 4 equiv.) was added, and the contents were stirred at

room temperature for 6 h in presence of air. The mixture was diluted with ethyl acetate (3 X 10

mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated over

vacuum. The residue was purified over a column of silica gel using ethyl acetate-hexane as the

eluent. The corresponding products 3a or 8a were formed in lower yields; and the yields were

found to decrease in a dose dependent manner as shown below.

S5

Concentration of TEMPO Yield of 3a Yield of 8a

1 equiv. 38% 28%

2 equiv. 28% 19%

3 equiv. 18% 8%

4 equiv. 10% No reaction

Procedure for the synthesis of N-trideuteromethyl-N-methyl aniline (1”) from N-methyl

aniline:

A round-bottomed flask was charged with paraformaldehyde-d2 (2.50 mmol) and sodium

hydroxide solution (1.4 mL of 40% aqueous sodium hydroxide solution) and placed in an ice-

water bath. The resulting white slurry was stirred for 15 min, and sulphuric acid (4.9 mL, 3M)

was added to it. To this solution, a mixture of N-methylaniline (0.83 mmol), sodium

borodeuteride-d4 (125 mg, 3.29 mmol) and tetrahydrofuran (7 mL) was added drop-wise over 10

min. The ice-water bath was removed and the contents were stirred for 3 h at room temperature.

After cooling again in an ice-water bath, 40% aqueous sodium hydroxide solution was added

drop-wise until the reaction mixture turned basic. The organic layer was successively washed

with 10 mL portions of water and brine and was dried over sodium sulphate. Filtration and

solvent removal in vacuum gave a yellow oil. Chromatography on silica gel using EtOAc/hexane

(5:95) as an eluent gave a dark brown solid on removing the solvent.

Reaction with deuterated analogs to study KH/KD:

CuBr catalyzed oxidative coupling reaction of N-trideuteriomethyl-N-methylaniline with 4-

methylphthalimide: Study of intramolecular deuterium isotope effect

S6

NH

O

O

N

CH3

CD3

+ N

O

O

N

H3C

CD2N

O

O

N

D3C

CH2+

CuBr 10 mol %, air

rt, CH3CN

An oven-dried microwave tube was charged with magnetic stirrer, N-trideuteriomethyl-N-

methylaniline (1’’) (0.17 mmol) and 4-methylphthalimide (7) (0.16 mmol) in acetonitrile as the

solvent. To it, CuBr (10 mol%) was added, and the contents were stirred at room temperature in

presence of air. Aliquots of the reaction mixture were taken out at 6 h and 12 h. The aliquot was

diluted with ethyl acetate (5 mL) and water was added. This mixture was extracted with ethyl

acetate and the combined organic layers were put together and dried upon Na2SO4. Solvents

were removed under reduced pressure, and the crude was re-dissolved in methanol and injected

in LC-MS (MRM analysis) to determine the relative yields of products.

Procedure for CuBr catalyzed oxidation of 4-chloro-N,N-dimethylaniline in presence of air

An oven-dried microwave tube was charged with magnetic stirrer, 4-chloro-N,N-

dimethylaniline (1 mmol) and acetonitrile as the solvent. To it, CuBr (10 mol%) was added, and

the contents were stirred at room temperature for 12 h in presence of air. The mixture was

extracted with ethyl acetate (3 X 10 mL), the combined organic layer was dried over anhydrous

Na2SO4 and concentrated over vacuum. The residue was purified over a column of silica gel

using ethyl acetate/hexane eluent to give two products; the structures of which were confirmed

by 1H NMR,

13C NMR spectral data.

S7

1-((Methyl(p-tolyl)amino)methyl)indoli-2-one (3a)

Brown solid, yield 88% (234 mg); (eluent: ethyl

acetate/Hexane =3/22); 1H NMR (300 MHz, CDCl3),

δ 7.15-7.11 (m, 1H), 7.05-6.99 (m, 3H), 6.92-6.87 (m,

1H), 6.80 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 7.8 Hz,

1H), 5.10 (s, 2H), 3.5 (s, 2H), 2.81 (s, 3H), 2.17 (s,

3H); 13

C NMR (75 MHz, CDCl3) δ 175.6, 146.7,

144.15, 129.9, 128.6, 127.9, 124.3, 124.2, 122.4,

115.4, 110.0, 58.8, 37.2, 36.0, 20.4; HR-MS (ESI)

m/z: Calcd for C17H18N2O [M + Na]+ 289.1311;

Found: 289.1318

1-(((4-methoxyphenyl)(methyl)amino)methyl)indolin-2-one (3b)

Red solid, yield 90% (253 mg); (eluent: ethyl

acetate/Hexane =4/21); 1H NMR (300 MHz, CDCl3),

δ 7.14 (d, J = 6.6, 1H), 7.06-7.01 (m, 1H), 6.93-6.88

(m, 3H), 6.79 (d, J = 8.7, 2H), 6.55 (d, J = 7.8, 1H),

5.06 (s, 2H), 3.71 (s, 3H), 3.51 (s, 2H), 2.80 (s, 3H);

13C NMR (75 MHz, CDCl3) δ 175.6, 153.8, 144.2,

143.4, 127.8, 124.2, 122.4, 118.0, 114.7, 110.0, 60.4,

59.9, 55.6, 37.9, 35.9; HR-MS (ESI) m/z : Calcd

C17H18N2O2 [M + Na]+ 305.1260 Found 305.1252

1-((methyl(phenyl)amino)methyl)indolin-2one (3c)

Pale Yellow solid, yield 60% (151 mg);(eluent: ethyl

acetate/Hexane = 14/86); 1H NMR (300 MHz,

CDCl3), δ 7.35-7.32 (m, 1H), 7.30-7.28 (m, 1H), 7.24

(d, J =7.2, 1H), 7.14 (t, J =7.8, 1H), 7.04-6.99 (m,

3H), 6.91-6.86 (m, 1H), 6.69 (d, J =7.8, 1H) 5.29 (s,

2H), 3.62 (s, 2H), 2.97 (s, 3H) 13

C NMR (75 MHz,

CDCl3) δ 175.6, 148.8, 143.9, 129.4, 127.9, 124.3,

124.2, 122.5, 119.0, 114.8, 109.9, 58.3, 37.0, 36.0;

HR-MS (ESI) m/z : Calcd C16H16N2O [M + Na]+

275.1154 ; Found 275.1154

S8

1-(((4-fluorophenyl)(methyl)amino)methyl)indolin-2-one (3d)

Pink solid, yield 70% (189 mg); (eluent: ethyl


CDCl3), δ 7.22 (d, J = 7.6, 1H), 7.13 (t, J = 7.6, 1H),

7.01-6.97 (m, 3H), 6.94-6.93 (m, 2H), 6.62 (d, J = 8,

1H), 5.17 (s, 2H), 3.58 (s, 2H), 2.91 (s, 3H); 13

C NMR

(75 MHz, CDCl3) δ 175.6, 156.9 (d, 1JCF = 237.1 Hz),

145.5, 143.9, 127.9, 124.4, 124.2, 122.5, 117.0, 116.9,

115.8 (d, 2JCF = 22.1 Hz), 109.8, 59.3, 37.8, 35.9; HR-

MS (ESI) m/z : Calcd C16H15FN2O [M + Na]+

293.1061; Found 293.1053

1-(((3-chlorophenyl)(methyl)amino)methyl)indolin-2-one (3e)

Brown solid, yield 77% (220mg); (eluent: ethyl

acetate/petrol ether =3/22); 1H NMR (300 MHz,

CDCl3), δ 7.15 (d, J = 7.5, 3H), 7.07 (t, J = 7.5, 1H),

6.93 (t, J = 7.5, 1H), 6.81 (d, J = 8.7 Hz, 2H), 6.58 (d,

J = 7.8, 1H), 5.14 (s, 2H), 3.50 (s, 2H), 2.87 (s, 3H);

13C NMR (75 MHz, CDCl3) δ 175.6, 147.3, 143.7,

129.8, 129.2, 127.9, 124.5, 124.2, 123.9, 122.6, 115.9,

109.7, 58.2, 37.4, 35.9; HR-MS (ESI) m/z : Calcd

C16H15ClN2O [M + Na]+

309.0765 Found 309.0753

1-(((4-bromophenyl)(methyl)amino)methyl)methyl)indolin-2one (3f)

Yellow solid, yield 80% (286 mg); (eluent: ethyl

acetate/Hexane = 4/21);1H NMR (400 MHz, CDCl3),

δ 7.38-7.35 (m, 2H), 7.23 (s, J = 7.2, 1H), 7.16 (t, J =

7.6, 1H), 7.01 (t, J = 7.2, 1H), 6.84 (d, J = 6.8, 2H),

6.66 (d, J = 7.6 MHz, 1H), 5.23 (s, 2H), 3.59 (s, 2H),

2.95 (s, 3H); 13

C NMR (75 MHz, CDCl3) δ 175.5,

147.6, 143.7, 132.1, 127.9, 124.5, 124.2, 122.6, 116.2,

111.1, 109.7, 57.9, 37.3, 35.9; HR-MS (ESI) m/z :

Calcd C16H15BrN2O [M + Na]+

353.0260 found

S9

353.0261

1-(((3-bromophenyl)(methyl)amino)methyl)indolin-2-one (3g)



δ 7.23 (d, J = 7.6, 1H), 7.12-7.18 (m, 2H), 7.06 (t, J

= 2.4, 1H), 7.04-6.99 (m, 1H), 6.97-6.95 (m, 1H),

6.91 (dd, J1 = 9.2, J1 = 2.8, 1H), 5.24 (s, 2H), 3.59 (s,

2H), 2.96 (3H); 13


149.8, 143.6, 130.5, 127.9, 124.5, 124.2, 123.5, 122.7,

121.6, 117.3, 112.9, 109.7, 57.6, 37.1, 35.9; HR-MS

(ESI) m/z : Calcd C16H15BrN2O [M + Na]+

353.0260

found 353.0261

1-(((3-chloroophenyl)(methyl)amino)methyl)indolin-2-one (3h)



CDCl3), δ 7.23-7.12 (m, 3H), 7.03-6.98 (m, 1H), 6.90-

6.79 (m, 3H), 6.67 (d, J = 7.8, 1H), 5.22 (s, 2H), 3.59

(s, 2H), 3.03 (s, 3H); 13

C NMR (75 MHz, CDCl3) δ

175.5, 149.7, 143.6, 135.2, 130.3, 127.9, 124.5, 124.2,

122.7, 118.6, 114.3, 112.4, 57.6, 37.1, 35.9; HR-MS

(ESI) m/z : Calcd C16H15ClN2O [M + Na]+

309.0765

Found 309.0752

1-((methyl(p-tolyl)amino)methyl)-3-(4-methylbenzylidene)indolin-2-one (4a)

Pale yellow solid, yield 81% (298 mg); (eluent: ethyl


δ 7.86 (s, 1H), 7.68 (d, J = 7.8, 1H), 7.56 (d, J = 7.8,

2H) 7.26 (d, J = 8.1, 2H), 7.12-7.06 (m, 3H), 6.91 (d,

J = 8.4, 2H), 6.86-6.34 (m, 2H), 6.67 (d, J = 7.8, 1H),

5.29 (s, 2H), 2.92 (s, 3H), 2.42 (s, 3H), 2.28 (s, 3H);

13C NMR (75 MHz, CDCl3) δ 169.1, 146.9, 143.0,

S10

140.0, 137.9, 132.0, 129.9, 129.6, 129.5, 129.4, 128.5,

126.4, 122.6, 121.8, 121.4, 115.5, 110.1, 58.8, 37.0,

21.6, 20.4; HR-MS (ESI) m/z : Calcd C25H24N2O [M

+ Na]+

391.1780 Found 391.1777

1-(((4-chlorophenyl)(methyl)amino)methyl)-3-(4-methylbenzylidene)indolin-2-one (4b)

Pale yellow solid, yield 81% (314 mg); (eluent: ethyl

acetate/Hexane = 1/24); 1H NMR (300 MHz, CDCl3),

δ 7.86 (s, 1H) 7.69 (d, J = 7.8, 1H), 7.59-7.54 (m,

2H), 7.29-7.22 (m, 3H), 7.12-7.11 (m, 1H), 6.94-6.85

(m, 3H), 6.64 (m, J = 8.1, 1H), 5.3 (d, J = 4.8, 2H),

2.96 (d, J = 5.1, 3H), 2.42 (d, J = 4.5, 3H); 13

C NMR

(75 MHz, CDCl3) 169.0, 147.4, 142.7, 140.2, 138.3,

131.9, 129.7, 129.5, 129.5, 129.4, 129.3, 129.2, 123.8,

122.8, 122.1, 121.5, 115.9, 115.9, 109.8, 58.2, 37.2,

37.1, 21.6; HR-MS (ESI) m/z : Calcd C24H22ClN2O

[M + Na]+

389.1415 Found 389.1424

(E)-3-(4-chlorobenzylidene)-1-(((4-chlorophenyl)(methyl)amino)methyl)indolin-2-one

(4c)

Pale Yellow solid, yield 80% (326 mg); (eluent: ethyl


7.78 (s, 1H), 7.61 (s, 1H), 7.49-7.53 (m, 2H), 7.39-

7.411(m, 2H), 7.24 (m, 1H), 7.15 (t, J = 8.7, 1H),

6.87-6.927 (m, 3H), 6.65 (d, J = 7.8), 5.30 (s, 2H),

2.97 (s, 3H) ;13

C NMR (75 MHz, CDCl3) 168.5,

147.3, 143.0, 136.6, 135.8, 134.7, 130.3, 130.1, 129.6,

129.5, 129.2, 128.9, 128.1, 127.3, 123.9, 122.9, 122.3,

120.8, 115.9, 110.0, 58.3, 37.2; HR-MS (ESI) m/z :

Calcd C23H18Cl2N2O [M + Na]+

431.0688 Found

431.0677

S11

2-((methyl(p-tolyl)amino)methyl)isoindoline-1,3-dione (6a)

Orange solid, yield 80% (236 mg); (eluent: ethyl


CDCl3), 7.62-7.57 (m, 1H), 7.42-7.38 (m, 1H), 7.08-

7.04 (m, 1H), 6.96-6.93 (m, 2H), 6.89-6.86 (m, 2H),

6.57 (d, J = 8, 1H), 5.17 (s, 2H), 3.79 (s, 3H) 2.88 (s,

3H); δ 13

C NMR (75 MHz, CDCl3) δ 183.4, 158.7,

154.3, 150.9, 142.8, 138.4, 125.3, 123.8, 118.6, 114.8,

112.1, 60.6, 55.6, 38.1; HR-MS (ESI) m/z : Calcd

C17H16N2O3 [M + Na]+

319.1053 Found 319.1054

1-(((4-fluorophenyl)(methyl)amino)methyl)indoline-2,3-dione (6b)



CDCl3),7.62-7.57 (m, 1H), 7.44 (t, J = 8, 1H), 7.13-

6.91 (m, 1H), 6.57 (d, J = 8.1, 1H), 5.22 (s, 2H), 2.96

(s, 3H); 13

C NMR (75 MHz, CDCl3) δ 183.2, 157.2 (d,

1JCF = 217.72 Hz), 150.6, 145.1, 138.6, 138.4, 125.8,

125.4, 123.9, 117.8 (d, 4JCF = 2.47 Hz), 117.6, 116.2

(d, 2JCF = 22.5 Hz), 112.3, 111.8, 59.9, 37.9; HR-MS

(ESI) m/z : Calcd C16H13FN2O2 [M + Na]+

307.0853

Found 307.0837

1-(((4-chlorophenyl)(methyl)amino)methyl)indoline-2,3-dione (6c)



CDCl3), δ 7.61 (d, J = 7.2, 1H), 7.46-7.44 (m, 1H),

7.26 (d, J = 9, 2H), 7.12-7.10 (m, 1H), 6.88 (d, J = 9,

2H), 6.65 (d, J = 7.8, 1H), 5.27 (s, 2H), 2.96 (s, 3H);

13C NMR (75 MHz, CDCl3) δ 183.0, 158.6, 150.3,

146.9, 138.5, 129.4, 125.7, 125.5, 124.8, 124.1, 123.9,

117.8, 116.4, 112.2, 111.7, 58.8, 37.5; HR-MS (ESI)

S12

m/z : Calcd C16H13ClN2O2 [M + Na]+

323.0557

Found 323.0558

1-(((4-bromophenyl)(methyl)amino)methyl)indoline-2,3-dione (6d)



δ 7.60 (d, J = 7.5, 1H), 7.49 (t, J = 7.5, 1H), 7.38 (d,

J = 8.7, 2H), 7.10 (t, J = 7.5, 1H), 6.83 (d, J = 8.7,

2H), 6.66 (d, J = 8.1, 1H), 5.26 (s, 2H), 2.96 (s, 3H);

13C NMR (75 MHz, CDCl3) δ 183.0, 158.5, 150.3,

147.2, 138.5, 132.3, 125.5, 124.1, 117.8, 116.7, 111.9,

117.7, 58.6, 37.4; HR-MS (ESI) m/z Calcd

C16H13BrN2O2 [M + Na]+

367.0052 Found 367.0055

5-bromo-1-(((4-bromophenyl)(methyl)amino)methyl)indoline-2,3-dione (6e)



δ 7.64 (s, 1H), 7.49 (d, J = 8.4, 1H), 7.32 (d, J = 8.4,

2H), 6.74 (d, J = 8.4, 2H), 6.45 (d, J = 8.4, 1H), 5.19

(s, 2H), 2.87 (s, 3H); 13


181.9, 157.8, 148.9, 147.2, 140.7, 132.4, 128.3, 118.9,

117.1, 116.8, 113.5, 112.2, 58.9, 37.4; HR-MS (ESI)

m/z : Calcd C16H12Br2N2O2 [M + Na]+

444.9157

Found 444.9137

2-((methyl(p-tolyl)amino)methyl)isoindoline-1,3-dione (8a)



δ 7.88-7.81 (m, 2H), 7.75-7.68 (m, 2H), 7.10-7.06 (m,

2H), 6.99-6.97 (m, 2H), 5.27 (d, J = 12, 2H), 3.14 (d,

J = 12, 3H), 2.26 (d, J = 11.7, 3H); 13

C NMR (75

MHz, CDCl3) δ 168.8, 145.2, 134.1, 132.1, 129.6,

127.7, 123.6, 123.4, 114.0, 56.8, 39.0, 20.3; HR-MS

S13

(ESI) m/z : Calcd C17H16N2O2 [M + Na]+

303.1103

Found 303.1103

2-(((4-methoxyphenyl)(methyl)amino)methyl)isoindoline-1,3-dione (8b)



δ 7.86-7.82 (m, 2H), 7.72-7.69 (m, 2H), 7.03 (d, J =

9, 2H), 6.85 (d, J = 9, 2H), 5.21 (s, 2H), 3.75 (s, 3H),

3.07 (s, 3H); 13


152.9, 141.9, 134.1, 132.0, 123.4, 115.9, 114.5, 57.5,

55.6, 39.1; HR-MS (ESI) m/z : Calcd C17H16N2O3 [M

+ Na]+

319.1053 Found 319.1065

2-(((4-fluorophenyl)(methyl)amino)methyl)-5-methylisoindoline-1,3-dione (8c)

Cream solid, yield 72% (201 mg); (eluent: ethyl


δ 7.88-7.83 (m, 2H), 7.77-7.71 (m, 2H), 7.05-6.95

(m, 4H), 5.25 (s, 2H), 3.12 (s, 3H); 13

C NMR (75

MHz, CDCl3) δ 168.7, 156.5 (d, 1JCF = 235.57 Hz),

143.9, 134.2, 131.9, 123.5, 115.5 (d, 2JCF = 22.5 Hz),

115.2 (d, 3JCF = 7.4 Hz), 57.1, 39.2; HR-MS (ESI)

m/z : Calcd C16H13FN2O2 [M + H]+

285.1033 Found

285.1025

2-(((4-chlorophenyl)(methyl)amino)methyl)isoindoline-1,3-dione (8d)



δ 7.86-7.83 (m, 2H), 7.74-7.73 (m, 2H), 7.20 (d, J =

9, 2H), 6.99 (d, J = 9, 2H), 5.25 (s, 2H), 3.14 (s, 3H);

13C NMR (75 MHz, CDCl3) δ 168.7, 145.9, 134.3,

131.9, 128.9, 123.5, 123.4, 114.9, 56.4, 39.1; HR-MS

(ESI) m/z : Calcd C16H13ClN2O2 [M + H]+

301.0738

S14

Found 301.0749.

2-(((4-bromophenyl)(methyl)amino)methyl)isoindoline-1,3-dione (8e)

White solid, yield 79% (271 mg); (eluent: ethyl


δ 7.86-7.83 (m, 2H), 7.73-7.71 (m, 2H), 7.33 (d, J =

9, 2H), 6.93 (d, J = 9, 2H); 5.24 (s, 2H), 3.14(s, 3H);

13C NMR (75 MHz, CDCl3) δ 168.7, 146.3, 134.3,

131.9, 131.8, 123.6, 115.3, 110.7, 56.2, 39.2; HR-MS

(ESI) m/z : Calcd C16H13BrN2O2 [M + H]+

345.0233

Found 345.0228

5-methyl-2-((methyl(p-tolyl)amino)methyl)isoindoline-1,3-dione (8f)



δ 7.69 (d, J = 7.5, 1H), 7.61(s, 1H), 7.47 (d, J = 7.5,

1H), 7.06 (d, J = 8.4, 2H), 6.97 (d, J = 8.7, 2H), 5.22

(s, 2H), 3.10 (s, 3H), 2.51 (s, 3H), 2.24 (s, 3H); 13

C

NMR (75 MHz, CDCl3) δ 168.9, 168.9, 145.4, 145.2,

134.7, 132.4, 129.7, 129.5, 127.6, 123.9, 123.33,

113.9, 56.7, 39.0, 22.0, 20.3; HR-MS [(ESI) m/z :

Calcd C18H18N2O2 317.1260 [M + Na]+

Found

317.1260

2-(((4-methoxyphenyl)(methyl)amino)methyl)-5-methylisoindoline-1,3-dione (8g)



δ 7.74-7.69, (m, 1H ), 7.63 (d, J = 9.6, 1H), 7.54-7.47

(m, 1H), 7.02 (d, J = 8.7, 2H), 6.84 (d, J = 8.7, 2H),

5.18 (s, 2H), 3.75 (s, 3H), 3.06 (s, 3H), 2.49 (s, 3H);

13C NMR (75 MHz, CDCl3) δ 169.0, 168.9, 152.9,

145.4, 141.9, 134.7, 132.4, 129.4, 124.1, 123.9, 123.4,

S15

115.9, 114.5, 57.4, 55.6, 39.1, 22.0. HR-MS (ESI) m/z

: Calcd C18H18N2O3 [M + Na]+

333.1209 Found

333.1207

2-(((4-fluorophenyl)(methyl)amino)methyl)-5-methylisoindoline-1,3-dione (8h)

Light brown solid, yield 74% (220 mg); (eluent: ethyl


δ 7.69 (d, J = 7.5, 1H), 7.6 ( s, 1H), 7.48 (d, J = 7.8,

1H), 6.99-6.92 (m, 4H), 5.18 (s, 2H), 3.09 (s, 3H),

2.49 (s, 3H); 13


168.8, 156.5 (d, 1JCF = 235.5 Hz), 145.6, 144.0, 134.8,

132.3, 129.3, 123.9, 123.4, 115.4 (d, 2JCF = 21.75 Hz),

115.2, 57.0, 39.1, 22.0. HR-MS (ESI) m/z : Calcd

C17H15FN2O2 [M + H]+

299.1190 Found 299.1186

2-(((4-chlorophenyl)(methyl)amino)methyl)-5-methylisoindoline-1,3-dione (8i)



δ 7.71(d, J = 7.8, 1H), 7.63 (s, 1H), 7.5 (d, 1H), 7.19

(d, J = 9, 2H,), 6.98 (d J = 9, 2H,), 5.22(s, 2H),

3.13(s, 3H), 2.5(s, 3H); 13


168.8, 168.6, 146.1, 145.6, 134.8, 132.3, 129.3,

128.9, 123.9, 123.3, 123.2, 114.8, 56.2, 39.0, 21.9;

HR-MS (ESI) m/z : m/z Calcd C17H15ClN2O2 [M +

H]+

315.0894 Found 315.0891

2-(((4-bromophenyl)(methyl)amino)methyl)-5-methylisoindoline-1,3-dione (8j)

Light brown solid, yield 81% (289 mg); (eluent: ethyl


δ 7.71 (d, J = 7.5, 1H), 7.63 (s, 1H), 7.50 (d, J = 7.8,

1H), 7.32 (d, J = 9, 2H), 6.93 (d, J = 9, 2H), 5.22 (s,

2H), 3.13 (s, 3H), 2.49 (s, 3H); 13

C NMR (75 MHz,

CDCl3) δ 168.9, 146.4, 145.6, 134.9, 134.8, 132.3,

S16

131.8, 129.3, 124.1, 123.5, 115.3, 110.6, 56.2, 39.1,

22.0; HR-MS (ESI) m/z : m/z Calcd C17H15BrN2O2

[M + Na]+

381.0209 Found 381.0219

5-methyl-2-((methyl(phenyl)amino)methyl)isoindoline-1,3-dione (8k)



δ 7.70 (d, J = 7.5, 1H), 7.63 (d, J = 0.9, 1H), 7.49

(dd, J1 = 7.8, J2 = 0.9, 1H), 7.30-7.24 (m, 2H), 7.07

(dd, J1 = 7.8, J2 = 0.9 2H), 6.80 (t, J1 = 7.8, H), 5.27

(s, 2H), 3.14 (s, 3H), 2.50 (s, 3H); 13

C NMR (75 MHz,

CDCl3) δ 168.9, 168.2, 147.4, 145.5, 134.7, 132.4,

129.4, 129.1, 123.9, 123.4, 118.3, 113.6, 56.4, 39.0,

22.0; HR-MS (ESI) m/z : m/z Calcd C17H16N2O2 [M

+ Na]+

303.1103 Found 303.1094

N-((methyl(p-tolyl)amino)methyl)benzamide (10a)

White crystal, yield 85% (215 mg); (eluent: ethyl


δ 7.71 (d, J = 7.2, 2H), 7.49-7.36 (m, 3H), 7.08 (d, J

= 8.1, 2H), 6.78 (d, J = 8.4, 2H), 6.61 (s, 1H), 5.07

(d, J = 5.7, 2H), 3.01 (s, 3H), 2.27 (s, 3H); 13

C NMR

(75 MHz, CDCl3) δ 167.9, 145.8, 134.2, 131.7, 130.0,

128.6, 127.7, 126.9, 113.8, 58.5, 38.1, 20.3; HR-MS

(ESI) m/z : m/z Calcd C16H18N2O [M + Na]+

277.1311 Found 277.1305

1-(((4-bromophenyl)(methyl)amino)methyl)piperidin-2-one (10b)

Brown liquid, yield 75% (222 mg); (eluent: ethyl


7.32-7.27 (m, 2H), 6.72-6.67 (m, 2H), 5.04 (s, 2H),

3.12 (s, 2H), 2.99 (s, 3H), 2.39 (s, 2H), 1.75-1.71(m,

4H); δ 13

C NMR (75 MHz, CDCl3) δ 170.2, 147.1,

S17

131.9, 131.5, 114.5, 109.8, 62.7, 45.6, 38.5, 32.4,

31.9, 22.9, 22.7; HR-MS (ESI) m/z : m/z Calcd

C13H17BrN2O [M + Na]+

319.0416 Found 319.0425

1-((methyl(p-tolyl)amino)methyl)azepan-2-one (10c)

Brown liquid, yield 79% (194 mg); (eluent: ethyl


CDCl3), δ 6.96 (d, J = 8.1, 2H), 6.65 (d, J = 8.4, 2H),

4.89 (s, 2H) 3.20-3.17 (m, 2H), 2.86 (s, 3H), 2.45 (s,

2H), 2.16 (s, 3H), 1.56 (s, 4H), 1.38 (s, 2H) ); 13

C

NMR (75 MHz, CDCl3) δ 176.5, 146.3, 129.8, 127.1,

113.6, 63.8, 46.8, 38.0, 37.5, 29.9, 28.1, 23.5, 20.3;

HR-MS (ESI) m/z : m/z Calcd C15H22N2O [M + Na]+

269.1624 Found 269.1618

1-(((4-bromophenyl)(methyl)amino)methyl)pyrrolidine-2,5-dione (10d)



δ 7.30 (d, J = 9, 2H), 6.86 (d, J = 9, 2H), 5.02 (s, 2H),

3.08 (s, 4H), 2.68 (s, 4H); 13

C NMR (75 MHz, CDCl3)

δ 177.6, 146.3, 131.8, 115.0, 110.6, 56.9, 39.5, 28.2;

HR-MS (ESI) m/z : Calcd C12H13BrN2O2 [M + Na]+

319.0052 Found 319.0054

1-((methyl(p-tolyl)amino)methyl)pyrrolidine-2,5-dione (10e)



CDCl3), δ 7.02 (d, J = 8.4, 2H), 6.87 (d, J = 8.7, 2H),

4.98 (s, 2H), 3.03 (s, 3H), 2.57 (s, 4H), 2.23 (s, 3H);

13C NMR (75 MHz, CDCl3) δ 177.8, 145.2, 129.7,

127.5, 113.6, 57.5, 39.4, 28.2, 20.3; LRMS (ESI) m/z

: Calcd C13H16N2O2 [M + Na]+

255.1104 Found

S18

255.1178

N-(((4-chlorophenyl)(methyl)amino)methyl)acetamide (10f)



CDCl3), δ 7.17 (d, J = 7.2, 2H), 6.71 (d, J = 7.5, 2H),

6.40 (NH), 4.81 (d, J = 5.4, 2H), 2.96 (s, 3H), 1.94

(s, 3H); 13

C NMR (75 MHz, CDCl3) δ 170.8, 146.5,

129.1, 122.9, 114.4, 57.5, 38.1, 23.1; HRMS (ESI)

m/z : Calcd C10H13ClN2O [M + Na]+

235.0609

Found 235.0612

S19

Crystallographic Description:

Data Collection and Refinement Single-crystal X-ray data of compounds was collected on

Bruker SMART CCD Diffractometer using graphite monochromated MoKα radiation (λ =

0.71073 Å). Frames were collected at T = 298 K by ω, φ, and 2θ-rotations with full quadrant data

collection strategy (four domains each with 600 frames) at 10s per frame with SMART. The

measured intensities were reduced to F2 and corrected for absorption with SADABS.

4 Structure

solution, refinement, and data output were carried out with the SHELXTL package by direct

methods.5 Non-hydrogen atoms were refined anisotropically using the WinGX (version 1.80.05)

program package.6 All non-hydrogen atoms were refined anisotropically and hydrogen atoms

were treated as riding atoms using SHELX default parameters. Molecular structures have drawn

using ORTEP software shown in figure S2. Further information on the crystal structure

determination (excluding structure factors) has been given as table S1 and also deposited in the

Cambridge Crystallographic Data Centre as supplementary publications no. 1459315. Copies of

the data can be obtained free of charge upon application to CCDC, 12 Union Road, Cambridge

CB2 1EZ, UK (fax: (+44) 1223-336-033. e-mail: [email protected]) or via internet.

S20

Figure S2 ORTEP diagram of 6d

Crystallographic description of 2-(((4-chlorophenyl)(methyl)amino)methyl)isoindoline-1,3-

dione (6d) (Table S1):

Identification code vi2m

Empirical formula C16H13ClN2O2

Formula weight 300.73

Temperature 298(2) K

Wavelength 0.71073 Å

Crystal system Monoclinic

Space group P21/c

Unit cell dimensions a = 7.7605(12) Å a= 90°.

b = 19.327(3) Å b= 101.584(3)°.

c = 9.6643(16) Å g = 90°.

Volume 1420.0(4) Å3

Z 4

Density (calculated) 1.407 Mg/m3

Absorption coefficient 0.274 mm-1

F(000) 624.0

S21

Crystal size 0.52 x 0.35 x 0.13 mm3

Theta range for data collection 2.11 to 25.00°.

Index ranges -6<=h<=9, -19<=k<=22, -

11<=l<=11

Reflections collected 6744

Independent reflections 2451 [R(int) = 0.0217]

Completeness to theta = 25.00° 98.0 %

Absorption correction None

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 2451 / 0 / 191

Goodness-of-fit on F2 1.039

Final R indices [I>2sigma(I)] R1 = 0.0405, wR2 = 0.0985

R indices (all data) R1 = 0.0546, wR2 = 0.1057

Largest diff. peak and hole 0.182 and -0.227 e.Å-3

CCDC 1459315

References:

1. Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 8928-8933.

2. Murata, S.; Miura, M.; Nomura, M. J. Chem. Soc., Chem. Commun. 1989, 116-118.

3. Murata, S.; Suzuki, K.; Tamatani, A.; Miura, M.; Nomura, M. J. Chem. Soc.,Perkin

Trans. 1992, 1387-1391.

4. SADABS V2.10 (Sheldrick, G. M. 2003).

5. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr., 1990, 46, 467.

6. Sheldrick, G. M. SHELXL-NT Version 6.12, University of Gottingen, Germany, 2000.

S22

1HNMR of Compound 3a

S23

13CNMR of Compound 3a

S24

1H NMR of Compound 3b

13CNMR of Compound 3b

S25

1HNMR of Compound 3c

13CNMR of Compound 3c

S26

1H NMR of Compound 3d

13CNMR of Compound 3d

S27

1HNMR of Compound 3e

13C NMR of Compound 3e

S28

1H NMR of Compound 3f

13C NMR of Compound 3f

S29

1H NMR of Compound 3g

13C NMR of Compound 3g

S30

1H NMR of Compound 3h

13C NMR of Compound 3h

S31

1H NMR of Compound 4a

13C NMR of Compound 4a

S32


13C NMR of Compound 4b

S33

1H NMR of Compound 4c

13C NMR of Compound 4c

S34



S35



S36

1H NMR of Compound 6c


S37

1H NMR of Compound 6d

13C NMR of Compound 6d

S38

1H NMR of Compound 6e

1H NMR of Compound 6e

S39



S40

1H NMR of compound 8b


S41

1H NMR of compound 8c


S42

1H NMR of compound 8d


S43

1H NMR of compound 8e

13C NMR of Compound 8e

S44

1H NMR of compound 8f

13C NMR of Compound 8f

S45

1H NMR of compound 8g

13C NMR of Compound 8g

S46

1H NMR of compound 8h

13C NMR of Compound 8h

S47

1H NMR of compound 8i

13C NMR of Compound 8i

S48

1H NMR of compound 8j

13C NMR of Compound 8j

S49

1H NMR of compound 8k

13C NMR of Compound 8k

S50

1H NMR of compound 10a


S51

1H NMR of compound 10b


S52

1H NMR of compound 10c


S53

1H NMR of compound 10d


S54

1H NMR of compound 10e

13C NMR of compound 10e

S55

1H NMR of compound 10f

13C NMR of compound 10f

S56

Spectra of Mechanistic Studies:

1H NMR of compound 1b’

1H NMR of compound 13

S57

1H NMR of compound 1’’

S58

LC-MS spectra of KH/KD experiment:

a) At 6 h of reaction time

Area of component Area Ratio Analyte Mass (Da) %

105039 15.3 284.300/123.200 83.431

20860 3.03 283.300/122.200 16.569

S59

b) At 12 h of reaction time

Area of

component

Area Ratio IS Area Analyte Mass (Da) %

16900000 15.6 1080000 284.300/123.200 85.2

2940000 2.71 1080000 283.300/122.200 14.8

Internal Standard

Internal Standard

Internal Standard

n-mannich bases of aromatic heterocyclic amides: synthesis

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