An efficient synthesis of 2-aminothiophenes via the gewald reaction catalyzed by an N-methylpiperazine-functionalized polyacrylonitrile fiber

Article abstract of DOI:10.1055/s-0032-1316821

A new N-methylpiperazine-functionalized polyacrylonitrile fiber has been developed to catalyze the Gewald reaction between 2,5-dihydroxy-1,4-dithiane and activated nitriles to afford 3-substituted 2-aminothiophenes in good to excellent yields (65-91%). Low catalyst loading (8.0 mol%), simple procedure, high yields, excellent recyclability, and reusability (up to 10 times with minimal loss of catalytic activity) are attractive features of this fiber catalyst. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316821

Journal of Synthetic 0rganic Chemistry
SUPPORTING INFORMATION
SYNTHESIS
Supporting Information
for DOI: 10.1055/s-0032-1316821
© Georg Thieme Verlag KG Stuttgart · New York 2012
Thieme

An Efficient Synthesis of 2-Aminothiophenes via the Gewald
Reaction Catalyzed by an N-methylpiperazine Functionalized
Polyacrylonitrile Fiber
Lichao Ma, Liwei Yuan, Changzhu Xu, Guowei Li, Minli Tao, Wenqin Zhang*
Department of Chemistry, School of Sciences, Tianjin University, No.92 Weijin Road,
Tianjin 300072, China.
Fax +86(22)27403475; E-mail: zhangwenqin@tju.edu.cn
Phone +86(22)27890922.
Table of Contents
General experimental information..........................................................................................S2
Acid exchange capacity of the fiber catalyst........................................................................S3
Synthesis of the activated nitriles...........................................................................................S4
References ...................................................................................................................................S9
NMR Spectra ............................................................................................................................S11
HRMS Spectra..........................................................................................................................S33
S1

General experimental information
Reagents
Commercially available polyacrylonitrile fiber (PANF) with a length of 10 cm and
diameter of 30±0.5 μm (from the Fushun Petrochemical Corporation of China) was used.
Water was deionized. All reagents were analytical grade. Acetonitrile was dried by CaH2.
Toluene was refluxed by sodium before use. Ethyl cyanoacetate, malononitrile,
2,5-dihydroxy-1,4-dithiane, N-methylpiperazine and the other reagents were used without
further purification. Column chromatography was performed on silica gel 200-300 mesh,
and the eluent was a mixture of petroleum ether (PE, bp 60-90 °C) and ethyl acetate
(EA).
.
S2

Acid exchange capacity of the fiber catalyst:
The acid exchange capacity was calculated according to the amount of acid consumed by
P-PANF. Dried P-PANF (0.250 g) was immersed in 20.00 mL of HCl solution (0.100 M)
for 6 h. Then the treated fiber was filtered out and washed with water. The concentration
of the remaining HCl solution was titrated by 0.100 M NaOH.
Entry
Weight of P-PANF
The consumed NaOH
Average
mL
Acid exchange capacity
mmol g-1
g
mL
1
2
3
0.250
0.250
0.250
14.25
14.20
14.20
14.21
2.32
The amount of acid consumed by P-PANF = 20.00 mL × 0.100 M – 14.21 mL × 0.100 M
= 0.579 mmol
The acid exchange capacity of P-PANF = 0.579 mmol ÷ 0.250 g = 2.32 mmol g-1
The determined acid exchange capacity of P-PANF was 2.32 mmol g-1, indicating that
1.000 g P-PANF contains 1.16 mmol 3-(N-methylpiperazinyl)propyl groups (each group
has two basic N atoms).
Unmodified PANF is composed by three parts: acrylonitrile (93.0%), methyl acrylate
(6.5%) and sodium styrene sulfonate (0.5%).
Each CN group in PANF reacted with an N-methyl-N’-(3-aminopropyl)piperazine
molecule and gets a ΔMW of 158.24 during the amination process. Each ester group
reacted with an amine molecule and gets a ΔMW of 125.21. If each CN group have the
same reaction opportunity as the ester group, we can give an average ΔMW = [158.24 ×
0.930 + 125.21 × 0.065] ÷ (0.930+0.065) = 156.08.
2.32 ÷ 2 ×156.08 = 0.181 g
0.181/ (1.000 – 0.181) = 22.1 %
The calculated weight gain of 22.1% is in accord with the measured weight gain of
23.0%.
S3

Synthesis of the activated nitriles
General procedure for synthesis of methyl carboxylate
A carboxylic acid (150 mmol) was dissolved in 150 mL of methanol. Then 7.5 mL of
concentrated sulfuric acid was added and the mixture was heated at reflux for 5 h. After
cooling to room temperature the reaction mixture was evaporated under vacuum. Then
100 mL of water was added and the residue was neutralized with NaHCO3. The mixture
was extracted by 200 mL of CH2C12. The organic layer was washed with H2O, 5%
aqueous NaHCO3, and saturated NaCl solution and dried over Na2SO4. Evaporate the
solvent to afford the desired product.1,2
(a) Methyl 2-methylbenzoate
1
Yield: 15.8 g, 70%; colorless oil; H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.4 Hz,
1H), 7.44 – 7.38 (m, 1H), 7.30 – 7.22 (m, 2H), 3.91 (s, 3H), 2.63 (s, 3H).3a
(b) Methyl 4-methylbenzoate
1
Yield: 21.2 g, 94%; white crystals; mp 30-32 °C (Lit.3b mp 35-36 °C); H NMR (400
MHz, CDCl3): δ = 7.93 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 3.90 (s, 3H), 2.40 (s,
3H).3b
(c) Methyl 4-chlorobenzoate
S4

Yield: 24.6 g, 96%; white crystals; mp 42-44 °C (Lit.2 mp 42-44 °C); 1H NMR (400 MHz,
CDCl3): δ = 7.97 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 3.91 (s, 3H).2
(d) Methyl 2-thiophenecarboxylate
1
Yield: 19.2 g, 90%; colorless oil; H NMR (400 MHz, CDCl3): δ = 7.81 – 7.77 (m, 1H),
7.55 – 7.51 (m, 1H), 7.10 – 7.06 (m, 1H), 3.87 (s, 3H).3c
(e) Methyl 2-naphthoate
Yield: 27.4 g, 98%; white solid; mp 74-75 °C (Lit.4a mp 75-77 °C); 1H NMR (400 MHz,
DMSO): δ = 8.63 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.05 – 7.97 (m, 3H), 7.70 – 7.58 (m,
2H), 3.92 (s, 3H).4b
Synthesis of methyl 4-methoxybenzoate5
Methyl 4-hydroxybenzoate (15.2 g, 100 mmol) was dissolved in 200 mL of dry DMF.
K2CO3 (49.8 g, 360 mmol) was added and the suspension was stirred for 30 min.
Methyliodide (14.4 g, 100 mmol) was then added dropwise. After stirring for 20 h, 200
mL of water was added. The precipitate was then filtered and washed with 100 mL of
cold water to afford the target product as a white solid (yield: 13.0 g, 78%). Mp 46-47 °C,
(Lit.5 mp 51-52 °C). 1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 8.8 Hz, 2H), 6.91 (d, J
= 8.8 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H).5
Synthesis of 2-cyano-N-phenylacetamide6
S5

Aniline (9.3 g, 100 mmol) was dissolved in 100 mL of DMF. Then ethyl cyanoacetate
(11.3 g, 100 mmol) was added and the mixture was heated at reflux for 6 h. And then 150
mL of water was added slowly. The precipitate was filtered and washed with cold water,
then recrystallized from ethanol to give the aimed product as a white solid (yield: 11.5 g,
1
72%). Mp. 195-196 °C (Lit.6b 193 °C). H NMR (400 MHz, DMSO): δ = 10.28 (s, 1H),
7.54 (d, J = 7.8 Hz, 2H), 7.37 – 7.29 (m, 2H), 7.09 (t, J = 7.4 Hz, 1H), 3.89 (s, 2H).6c
Synthesis of 2-cyanoacetamide7
Ethyl cyanoacetate (5.7 g, 50 mmol) was dropped into 49 mL of aqueous ammonia (25%).
The mixture was stirred for 1 h; then warms up a little. The flask was allowed to stand 2 h
in an ice-salt mixture. The precipitate was filtered and washed with cold ethanol, then
recrystallized from 95% ethanol to give the 2-cyanoacetamide as a white solid (yield: 1.6
1
g, 38%). Mp 113 °C (Lit.7a mp 119-120 °C). H NMR (400 MHz, DMSO): δ = 7.63 (s,
1H), 7.32 (s, 1H), 3.57 (s, 2H).7b
General procedure for synthesis of benzoylacetonitriles and other activated nitriles
Method A. An ester (100 mmol) and acetonitrile (12.5 mL, 300 mmol) were dissolved in
100 mL of toluene, then sodium hydride (80%, 9.0 g, 300 mmol) was added and the
reaction mixture was heated to reflux for 24 h. After cooling to room temperature, it was
filtered and washed with 30 mL of CH2Cl2. The solid material was dissolved in 100 mL
of water and cooling ice/salt mixture. Then HCl 15% was added until pH = 2-3 and in a
manner that its temperature shall not exceed 5 °C. The precipitate was filtered and
washed with water until neutral, then recrystallized from ethanol to give the desired
product.8
S6

Method B. An ester (100 mmol) was dissolved in 200 mL of dry acetonitrile. Sodium
methoxide (10.8 g, 200 mmol) was added and the reaction mixture was heated at reflux
under the protection of nitrogen for 6 h. After cooling to room temperature, 200 mL of
H2O was added and the reaction mixture was washed with CH2Cl2 (3×150 mL). The
aqueous layer was adjusted to pH = 7 using 10% aq citric acid and the product
precipitated upon standing. The precipitate was filtered and then recrystallized from
ethanol to give the target product.2
(a) Benzoylacetonitrile (Method A)
1
Yield: 9.6 g, 66%; light yellow crystals; mp 75-76 °C (Lit.8b mp 81 °C). H NMR (400
MHz, CDCl3): δ = 7.91 (d, J = 7.6 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.56 – 7.49 (m, 2H),
4.14 (s, 2H).9
(b) 2-Methylbenzoylacetonitrile (Method A)
1
Yield: 10.7 g, 67%; light yellow crystals; mp 78-79 °C (Lit.9 mp 86-88 °C). H NMR
(400 MHz, CDCl3): δ = 7.63 (d, J = 7.6 Hz, 1H), 7.51 – 7.45 (m, 1H), 7.36 – 7.29 (m,
2H), 4.07 (s, 2H), 2.57 (s, 3H).9
(c) 4-Chlorobenzoylacetonitrile (Method B)
S7

1
Yield: 12.6 g, 70%; light yellow crystals; mp 125-126 °C (Lit.2 mp 126-128 °C). H
NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.09 (s,
2H).2
(d) 4-Methylbenzoylacetonitrile (Method B)
1
Yield: 9.7 g, 61%; white crystals; mp 100-101 °C (Lit.8c mp 94-96 °C). H NMR (400
MHz, CDCl3): δ = 7.82 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 4.06 (s, 2H), 2.44 (s,
3H).9
(e) 4-Methoxybenzoylacetonitrile (Method B)
1
Yield: 8.8 g, 50%; white crystals; mp 128-129 °C (Lit.9 mp 123-126 °C). H NMR (400
MHz, CDCl3): δ = 7.90 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 4.03 (s, 2H), 3.90 (s,
3H).9
(f) 2-Thiophenoylacetonitrile (Method A)
Yield: 8.5 g, 56%; light yellow crystals; mp 123-126 oC; (Lit.10 mp 124-126 °C). 1H
NMR (400 MHz, CDCl3): δ = 7.79 – 7.70 (m, 2H), 7.19 – 7.11 (m, 1H), 4.02 (s, 2H).10
(g) 2-Furoylacetonitrile (Method A)
S8

Yield: 8.1 g, 60%; light yellow crystals; mp 66-68 °C (Lit.10 mp 66-68 °C). 1H NMR (400
MHz, CDCl3): δ = 7.67 (s, 1H), 7.39 (d, J = 3.3 Hz, 1H), 6.65 (dd, J = 1.7, 1.6 Hz, 1H),
3.98 (s, 2H).10
(h) 2-Naphthoylacetonitrile (Method A)
1
Yield: 9.8 g, 50%; yellow crystals; mp 122-123 °C (Lit.11 mp 124 °C). H NMR (400
MHz, DMSO): δ = 8.66 (s, 1H), 8.15 – 7.93 (m, 4H), 7.74 – 7.63 (m, 2H), 4.91 (s, 2H).11
Synthesis of tosylacetonitrile12
A mixture of sodium 4-methylbenzenesulfinate (8.9 g, 50 mmol) and 2-chloroacetonitrile
(5.7 g, 75 mmol) was stirred at 60 °C for 2 h in 20 mL of PEG-400. The reaction mixture
was poured into 300 mL of water. The precipitate was filtered and washed with cold
ethanol, then recrystallized from ethanol to give the desired product as a light yellow
1
solid (yield: 8.7 g, 89%). Mp: 144-146 °C (Lit.12a 147-148 °C). H NMR (400 MHz,
CDCl3): δ = 7.91 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 4.05 (s, 2H), 2.50 (s,
3H).12b
References
(1)
(2)
Anzalone, L.; Hirsch, J. A. J. Org. Chem. 1985, 50, 2128.
Moe, S. T.; Thompson, A. B.; Smith, G. M.; Fredenburg, R. A.; Stein, R. L.; Jacobson, A. R. Bioorg. Med. Chem.
2009, 17, 3072.
(3)
(4)
(5)
(a) Heller, S. T.; Sarpong, R.; Org. Lett. 2010, 12, 4572. (b)Tank, R.; Pathak, U.; Vimal, M.; Bhattacharyya, S.;
Pandey, L. K. Green Chem. 2011, 13, 3350. (c) Sarkar, S. D.; Grimme, S.; Studer, A. J. AM. CHEM. SOC. 2010,
132, 1190.
(a) Yamamoto, Y. Adv. Synth. Catal. 2010, 352, 478. (b) Avila, C. M.; Lopes, A. B.; Gonçalves, A. S.; Silva, L.
L.; Nelilma C. Romeiro, N. C.; Miranda, A. L. P.; Sant’Anna, C. M. R.; Barreiro, E. J.; Fraga, C. A. M. Eur. J.
Med. Chem. 2011, 46, 1245.
Andrews, P. C.; Beck, T.; Fraser, B. H.; Junk, P. C.; Massi, M.; Moubaraki, B.; Murray, K. S.; Silberstein, M.
Polyhedron 2009, 28, 2123.
S9

(6)
(a) Adhikari, R.; Jones, D. A.; Liepa, A. J.; Nearn, R. H. Aust. J. Chem. 2005, 58, 882. (b) Poradosu, E.; Gazit,
A.; Reuveni, H.; Levitzki, A. Bioorg. Med. Chem. 1999, 7, 1727. (c) Guo, D.; Chen, T.; Ye, D.;Xu, J.; Jiang, H;
Chen, K.; Wang, H.; Liu, H. Org. Lett. 2011, 13, 2884.
(7)
(8)
(9)
(a) Corson, B. B.; Scott, R. W.; Vose, C. E. Organic Syntheses, Coll. 1941, 1, 179; 1929, 9, 36. (b) Exner, J. H.;
Burk, G. A.; Kyriacou, D. J. Agric. Food Chem. 1973,21,838.ꢀ
(a) Yu, W. Q.; Du, Y. F.; Zhao, K. Org. Lett, 2009, 11, 2417. (b) Ji, Y. H.; Trenkle, W. C.; Vowles, J. V. Org. Lett.,
2006, 8, 1161. (c) Burgaz, E. V.; Yılmaz, M.; Pekela, A. T.; Öktemera, A. Tetrahedron 2007, 63, 7229.ꢀ
Park, A.; Lee, S. Org. Lett, 2012, 14, 1118.
(10) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem. 2003, 68, 4932.
(11) Baraldi,P. G.; Romagnoli, R.; Pavani, M. G.; Nu³ez, M. C.; Tabrizi, M. A.; Shryock, J. C.; Leung, E.; Moorman,
A. R.; Uluoglu, C.; Iannotta, V.; Merighi, S.; Borea, P. A. J. Med. Chem. 2003, 46, 794.
(12) (a) Sukata. K. Bull. Chem. Soc. Jpn. 1984, 57, 613. (b) Bram, G.; Loupy, A.; Roux-Schmitt, M. C.; Sansoulet, J.;
Strzalko, T.; Seyden-Penne, J. Synthesis 1987, 56.
S10

NMR Spectra
S11

N-methyl-N’-(3-aminopropyl)piperazine
The 1H NMR spectrum of N-methyl-N’-(3-aminopropyl)piperazine
The 13C NMR spectrum of N-methyl-N’-(3-aminopropyl)piperazine
S12

2-Cyano-N-phenylacetamide
The 1H NMR spectrum of 2-Cyano-N-phenylacetamide
2-Cyanoacetamide
The 1H NMR spectrum of 2-cyanoacetamide
S13

Benzoylacetonitrile
The 1H NMR spectrum of benzoylacetonitrile
2-Methylbenzoylacetonitrile
The 1H NMR spectrum of 2-methylbenzoylacetonitrile
S14

4-Chlorobenzoylacetonitrile
The 1H NMR spectrum of 4-chlorobenzoylacetonitrile
4-Methylbenzoylacetonitrile
The 1H NMR spectrum of 4-methylbenzoylacetonitrile
S15

4-Methoxybenzoylacetonitrile
The 1H NMR spectrum of 4-methoxybenzoylacetonitrile
2-Thiophenoylacetonitrile
The 1H NMR spectrum of 2-thiophenoylacetonitrile
S16

2-Furoylacetonitrile
The 1H NMR spectrum of 2-furoylacetonitrile
2-Naphthoylacetonitrile
The 1H NMR spectrum of 2-naphthoylacetonitrile
S17

Tosylacetonitrile
The 1H NMR spectrum of tosylacetonitrile
S18

Ethyl 2-aminothiophene-3-carboxylate (5a, Table 5, Entry 1)
The 1H NMR spectrum of ethyl 2-aminothiophene-3-carboxylate
The 13C NMR spectrum of ethyl 2-aminothiophene-3-carboxylate
S19

2-Aminothiophene-3-carbonitrile (5b, Table 5, Entry 2)
The 1H NMR spectrum of 2-aminothiophene-3-carbonitrile
The 13C NMR spectrum of 2-aminothiophene-3-carbonitrile
S20

2-Aminothiophene-3-carboxamide (5c, Table 5, Entry 3)
The 1H NMR spectrum of 2-aminothiophene-3-carboxamide
The 13C NMR spectrum of 2-aminothiophene-3-carboxamide
S21

2-Amino-N-phenylthiophene-3-carboxamide (5d, Table 5, Entry 4)
The 1H NMR spectrum of 2-amino-N-phenylthiophene-3-carboxamide
The 13C NMR spectrum of 2-amino-N-phenylthiophene-3-carboxamide
S22

2-Amino-3-benzoylthiophene (5e, Table 5, Entry 5)
The 1H NMR spectrum of 2-amino-3-benzoylthiophene
The 13C NMR spectrum of 2-amino-3-benzoylthiophene
S23

2-Amino-3-(2-methylbenzoyl)thiophene (5f, Table 5, Entry 6)
The 1H NMR spectrum of 2-amino-3-(2-methylbenzoyl)thiophene
The 13C NMR spectrum of 2-amino-3-(2-methylbenzoyl)thiophene
S24

2-Amino-3-(4-methylbenzoyl)thiophene (5g, Table 5, Entry 7)
The 1H NMR spectrum of 2-amino-3-(4-methylbenzoyl)thiophene
The 13C NMR spectrum of 2-amino-3-(4-methylbenzoyl)thiophene
S25

2-Amino-3-(4-methoxybenzoyl)thiophene (5h, Table 5, Entry 8)
The 1H NMR spectrum of 2-amino-3-(4-methoxybenzoyl)thiophene
The 13C NMR spectrum of 2-amino-3-(4-methoxybenzoyl)thiophene
S26

2-Amino-3-(4-chlorobenzoyl)thiophene (5i, Table 5, Entry 9)
The 1H NMR spectrum of 2-amino-3-(4-chlorobenzoyl)thiophene
The 13C NMR spectrum of 2-amino-3-(4-chlorobenzoyl)thiophene
S27

2-Amino-3-(2,2-dimethylpropanoyl)thiophene (5j, Table 5, Entry 10)
The 1H NMR spectrum of 2-amino-3-(2,2-dimethylpropanoyl)thiophene
The 13C NMR spectrum of 2-amino-3-(2,2-dimethylpropanoyl)thiophene
S28

2-Amino-3-(2-thiophenoyl)thiophene (5k, Table 5, Entry 11)
The 1H NMR spectrum of 2-amino-3-(2-thiophenoyl)thiophene
The 13C NMR spectrum of 2-amino-3-(2-thiophenoyl)thiophene
S29