n-mannich bases of aromatic heterocyclic amides: synthesis

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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 k H /k D S5-S6 8. Procedure for oxidation of 4-chloro-N,N-dimethylaniline with air in the presence of CuBr S6 9. Spectral data: 1 H NMR, 13 C{1H} NMR, and HRMS S7-S18 10. Crystallographic Description S19-S20 11. References S21 12. Spectra: 1 H NMR, 13 C{1H} NMR S22-S54 13. Spectra of Mechanistic Studies S55-S56 14. LC-MS spectra of k H /k D experiment S57-S58

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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*
*E-mail: [email protected]; Fax: +91 11 26581102; Tel: +91 11 26591562
# equal contribution
S2
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-S5
6.
N-methylaniline
S5
S5-S6
8.
presence of CuBr
S7-S18
S55-S56
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
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 1 H NMR,
13 C{1H} NMR, and HRMS data. NMR
spectra for all the samples were taken in deuterochloroform (CDCl3) and dimethylsufoxide-d6
(DMSO-d6) as the solvents. 1 H and
13 C-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. 1 H 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 1 H NMR, and
13 C 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 1 H NMR,
13 C 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
1 equiv. 38% 28%
2 equiv. 28% 19%
3 equiv. 18% 8%
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
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 1 H NMR,
S7
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
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)
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);
13 C 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)
acetate/Hexane = 14/86); 1 H 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,
HR-MS (ESI) m/z : Calcd C16H16N2O [M + Na] +
275.1154 ; Found 275.1154
acetate/Hexane = 11/89); 1 H 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, 1 JCF = 237.1 Hz),
145.5, 143.9, 127.9, 124.4, 124.2, 122.5, 117.0, 116.9,
115.8 (d, 2 JCF = 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
acetate/petrol ether =3/22); 1 H 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);
13 C 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
Yellow solid, yield 80% (286 mg); (eluent: ethyl
acetate/Hexane = 4/21); 1 H 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
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] +
Yellow solid, yield 81% (231 mg); (eluent: ethyl
acetate/Hexane = 4/21); 1 H 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
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
acetate/Hexane = 13/87); 1 H 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
acetate/Hexane = 5/95); 1 H 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);
13 C NMR (75 MHz, CDCl3) δ 169.1, 146.9, 143.0,
S10
+ Na] +
acetate/Hexane = 1/24); 1 H 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
37.1, 21.6; HR-MS (ESI) m/z : Calcd C24H22ClN2O
[M + Na] +
acetate/Hexane = 5/95); 1 H 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
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] +
acetate/Hexane = 22/78); 1 H 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
C17H16N2O3 [M + Na] +
319.1053 Found 319.1054
acetate/Hexane = 18/82); 1 H 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
1JCF = 217.72 Hz), 150.6, 145.1, 138.6, 138.4, 125.8,
125.4, 123.9, 117.8 (d, 4 JCF = 2.47 Hz), 117.6, 116.2
(d, 2 JCF = 22.5 Hz), 112.3, 111.8, 59.9, 37.9; HR-MS
(ESI) m/z : Calcd C16H13FN2O2 [M + Na] +
307.0853
acetate/Hexane = 18/82); 1 H 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);
13 C 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
323.0557
Orange solid, yield 79% (467 mg); (eluent: ethyl
acetate/Hexane = 5/20); 1 H 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);
13 C 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
Orange solid, yield 80% (336 mg); (eluent: ethyl
acetate/Hexane = 5/20); 1 H 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
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
S13
303.1103
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] +
(m, 4H), 5.25 (s, 2H), 3.12 (s, 3H); 13
C NMR (75
MHz, CDCl3) δ 168.7, 156.5 (d, 1 JCF = 235.57 Hz),
143.9, 134.2, 131.9, 123.5, 115.5 (d, 2 JCF = 22.5 Hz),
115.2 (d, 3 JCF = 7.4 Hz), 57.1, 39.2; HR-MS (ESI)
m/z : Calcd C16H13FN2O2 [M + H] +
285.1033 Found
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);
13 C 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
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);
13 C 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
Yellow solid, yield 85% (249 mg); (eluent: ethyl
acetate/Hexane = 6/94); 1 H 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
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
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);
13 C 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
: Calcd C18H18N2O3 [M + Na] +
acetate/Hexane = 6/94); 1 H 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
168.8, 156.5 (d, 1 JCF = 235.5 Hz), 145.6, 144.0, 134.8,
132.3, 129.3, 123.9, 123.4, 115.4 (d, 2 JCF = 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
Yellow solid, yield 79% (248 mg); (eluent: ethyl
acetate/Hexane = 6/94); 1 H 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] +
acetate/Hexane = 2/23); 1 H 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,
S16
22.0; HR-MS (ESI) m/z : m/z Calcd C17H15BrN2O2
[M + Na] +
White solid, yield 65% (182 mg); (eluent: ethyl
acetate/Hexane = 6/94); 1 H 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,
+ Na] +
White crystal, yield 85% (215 mg); (eluent: ethyl
acetate/Hexane = 5/20); 1 H 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
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
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
S17
C13H17BrN2O [M + Na] +
319.0416 Found 319.0425
acetate/Hexane = 18/78); 1 H 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
HR-MS (ESI) m/z : m/z Calcd C15H22N2O [M + Na] +
269.1624 Found 269.1618
White solid, yield 88% (260 mg); (eluent: ethyl
acetate/Hexane = 3/22); 1 H 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
acetate/Hexane = 14/86); 1 H 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);
13 C 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] +
acetate/Hexane = 35/65); 1 H 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
m/z : Calcd C10H13ClN2O [M + Na] +
235.0609
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 F 2 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
Crystallographic description of 2-(((4-chlorophenyl)(methyl)amino)methyl)isoindoline-1,3-
b = 19.327(3) Å b= 101.584(3)°.
c = 9.6643(16) Å g = 90°.
Volume 1420.0(4) Å3
11<=l<=11
Reflections collected 6744
Absorption correction None
Goodness-of-fit on F2 1.039
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
S23
S24
13 CNMR of Compound 3b
S25
S26
13 CNMR of Compound 3d
S27
13 C NMR of Compound 3e
S28
S29
S30
S31
S32
S33
S34
S35
S36
S37
S38
S39
S40
S41
S42
S43
S44
S45
S46
S47
S48
S49
S50
S51
S52
S53
S54
S55
S56
S57
S58
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
Area of
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