Post on 18-Feb-2022
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: njain@chemistry.iitd.ac.in; 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
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
acetate/Hexane = 11/89); 1H NMR (400 MHz,
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)
Yellow solid, yield 81% (231 mg); (eluent: ethyl
acetate/Hexane = 4/21);1H NMR (400 MHz, CDCl3),
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
C NMR (75 MHz, CDCl3) δ 175.6,
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)
Brown solid, yield 75% (214 mg); (eluent: ethyl
acetate/Hexane = 13/87); 1H NMR (300 MHz,
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
acetate/Hexane = 5/95);1H NMR (300 MHz, CDCl3),
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
acetate/Hexane = 5/95); 1H NMR (300 MHz, CDCl3),
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
acetate/Hexane = 22/78); 1H NMR (300 MHz,
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)
Orange solid, yield 75% (213 mg); (eluent: ethyl
acetate/Hexane = 18/82); 1H NMR (300 MHz,
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)
Orange solid, yield 78% (234 mg); (eluent: ethyl
acetate/Hexane = 18/82); 1H NMR (300 MHz,
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)
Orange solid, yield 79% (467 mg); (eluent: ethyl
acetate/Hexane = 5/20); 1H NMR (300 MHz, CDCl3),
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)
Orange solid, yield 80% (336 mg); (eluent: ethyl
acetate/Hexane = 5/20); 1H NMR (300 MHz, CDCl3),
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
C NMR (75 MHz, CDCl3) δ
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)
Yellow solid, yield 81% (226 mg); (eluent: ethyl
acetate/Hexane = 6/94); 1H NMR (300 MHz, CDCl3),
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)
Brown solid, yield 85% (251 mg); (eluent: ethyl
acetate/Hexane = 2/23); 1H NMR (300 MHz, CDCl3),
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
C NMR (75 MHz, CDCl3) δ 168.8,
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
acetate/Hexane = 5/85); 1H NMR (300 MHz, CDCl3),
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)
Yellow solid, yield 77% (231 mg); (eluent: ethyl
acetate/Hexane = 6/94); 1H NMR (300 MHz, CDCl3),
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
acetate/Hexane = 2/23); 1H NMR (300 MHz, CDCl3),
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)
Yellow solid, yield 85% (249 mg); (eluent: ethyl
acetate/Hexane = 6/94); 1H NMR (300 MHz, CDCl3),
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)
Yellow solid, yield 89% (275 mg); (eluent: ethyl
acetate/Hexane = 2/23); 1H NMR (300 MHz, CDCl3),
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
acetate/Hexane = 6/94); 1H NMR (300 MHz, CDCl3),
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
C NMR (75 MHz, CDCl3) δ 168.9,
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)
Yellow solid, yield 79% (248 mg); (eluent: ethyl
acetate/Hexane = 6/94); 1H NMR (300 MHz, CDCl3),
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
C NMR (75 MHz, CDCl3) δ
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
acetate/Hexane = 2/23); 1H NMR (300 MHz, CDCl3),
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)
White solid, yield 65% (182 mg); (eluent: ethyl
acetate/Hexane = 6/94); 1H NMR (300 MHz, CDCl3),
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
acetate/Hexane = 5/20); 1H NMR (300 MHz, CDCl3),
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
acetate/Hexane = 4/21); 1H NMR (300 MHz, CDCl3),
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
acetate/Hexane = 18/78); 1H NMR (300 MHz,
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)
White solid, yield 88% (260 mg); (eluent: ethyl
acetate/Hexane = 3/22); 1H NMR (300 MHz, CDCl3),
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)
White solid, yield 91% (211 mg); (eluent: ethyl
acetate/Hexane = 14/86); 1H NMR (300 MHz,
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)
Brown solid, yield 87% (184 mg); (eluent: ethyl
acetate/Hexane = 35/65); 1H NMR (300 MHz,
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: deposit@ccdc.cam.ac.uk) 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
1H NMR of Compound 4b
13C NMR of Compound 4b
S33
1H NMR of Compound 4c
13C NMR of Compound 4c
S34
1H NMR of Compound 6a
13C NMR of Compound 6a
S35
1H NMR of Compound 6b
13C NMR of Compound 6b
S36
1H NMR of Compound 6c
13C 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
1H NMR of Compound 8a
13C NMR of Compound 8a
S40
1H NMR of compound 8b
13C NMR of Compound 8b
S41
1H NMR of compound 8c
13C NMR of Compound 8c
S42
1H NMR of compound 8d
13C 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
13C NMR of Compound 10a
S51
1H NMR of compound 10b
13C NMR of Compound 10b
S52
1H NMR of compound 10c
13C NMR of Compound 10c
S53
1H NMR of compound 10d
13C 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