LETTER
Aryl Alkyl Ketones in a One-Pot Gewald Synthesis of 2-Aminothiophenes
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(12) Ionic liquids were shown to be very efficient in the case of
the Gewald synthesis with aliphatic and alicyclic ketones:
Hu, Y.; Chen, Z.-C.; Le, Z.-G.; Zheng, Q.-G. Synth.
Commun. 2004, 34, 3801.
(13) To dissolve crystalline ammonium salts a small amount of
95% ethanol was added (0.5 mL per 1 mmol of
acetophenone). DMF was also shown to be a good choice.
(14) Replacement of morpholine with alternative amines or
acetic acid with TFA caused a substantial drop in the
conversion of acetophenone. Thus, changing the amine from
morpholine to diethylamine produced a heavily
organic layer was separated, filtered through a short plug of
silica, and concentrated in vacuo to give 2a (3.14 g, 64%.
1H NMR (400 MHz, CDCl3): d = 0.92 (t, 3 H, J = 7.2 Hz,
CH3CH2O), 4.02 (q, 2 H, J = 7.2 Hz, CH3CH2O), 5.58 (br s,
2 H, NH2), 6.04 (s, 1 H, thiophene-CH), 7.28 (app s, 5 H,
ArH). 13C NMR (400 MHz, CDCl3): d = 13.61 (q), 59.38 (t),
105.47 (d), 106.31 (s), 126.74 (d), 127.18 (d), 128.91 (d),
138.46 (s), 141.68 (s), 163.70 (s), 165.66 (s). HRMS: m/z
calcd for C13H13NO2S [M+]: 247.0667; found: 247.0678.
Thiophenes 2b–n were prepared analogously.
Compound 2b: Purified by method A (CH2Cl2); yield: 56%;
white powder; mp 105–107 °C (EtOH). 1H NMR (400 MHz,
CDCl3): d = 0.97 (t, 3 H, J = 7.2 Hz, CH3CH2O), 4.04 (q, 2
H, J = 7.2 Hz, CH3CH2O), 5.94 (br s, 2 H, NH2), 6.04 (s, 1
H, thiophene-CH), 7.21 (d, AB system, 2 H, J = 8.8 Hz,
ArH), 7.25 (d, AB system, 2 H, J = 8.8 Hz, ArH). 13C NMR
(400 MHz, CDCl3): d = 13.63 (q), 59.40 (t), 105.64 (d),
105.76 (s), 127.23 (d), 130.14 (d), 132.59 (s), 136.82 (s),
140.21 (s), 163.86 (s), 165.34 (s). HRMS: m/z calcd for
C13H12NO2SCl [M+]: 281.0277; found: 281.0281.
Compound 2c: Purified by method B; yield: 52%; white
powder; mp 120–121 °C (hexane). 1H NMR (400 MHz,
CDCl3): d = 0.96 (t, 3 H, J = 7.2 Hz, CH3CH2O), 4.04 (q, 2
H, J = 7.2 Hz, CH3CH2O), 5.88 (br s, 2 H, NH2), 6.02 (s, 1
H, thiophene-CH), 7.14 (d, 2 H, J = 8.4 Hz, ArH), 7.41 (d, 2
H, J = 8.4 Hz, ArH). 13C NMR (400 MHz, CDCl3):
d = 13.67 (q), 59.44 (t), 105.65 (d), 105.73 (s), 120.72 (s),
130.21 (d), 130.51 (d), 137.31 (s), 140.23 (s), 163.89 (s),
165.35 (s). HRMS: m/z calcd for C13H12NO2SBr [M+]:
324.9773; found: 324.9791.
contaminated reaction mixture with only 18% conversion.
At the same time employing half the amount of morpholine
(1.5 equiv) and acetic acid (0.5 equiv) with acetophenone
cyanoacetate (1 equiv) and sulfur (1 equiv) resulted in only
a small decrease in ketone conversion (57%).
(15) Peet, N. P.; Sunder, S.; Barbuch, R. J. J. Heterocycl. Chem.
1986, 23, 129.
(16) Resonances of methyl groups adjacent to double bonds in
authentic (E)- and (Z)-nitriles 3a: Zhu, X.-Q.; Liu, Y.-C.; Li,
J.; Wang, H.-Y. J. Chem. Soc., Perkin Trans. 2 1997, 2191.
(17) We were also interested in investigating if the combination
of organic base and acid were essential for the formation of
3a and if we could reach a similar equilibrium in the absence
of acetic acid, that is, under conditions generally used in
classical one-pot Gewald reaction (see ref. 1). In contrast to
the former experiment, even heating for 12 hours was
insufficient for the mixture of acetophenone, ethyl cyano-
acetate, and morpholine (1:1:3) to give any condensation
products at detectable concentrations. The same result was
obtained for the reaction of acetophenone, ethyl cyano-
acetate, and acetic acid in the absence of morpholine. Kinetic
measurements and further experiments made it possible to
consider that the acid–base ‘catalyst’, morpholinium acetate,
was required in high concentrations to enhance the rate of
the process leading to nitriles 3a, which in turn was a key
intermediate for the latter steps of thiolation and ring
closure.
Compound 2d: Purified by method B; yield: 70%; white
powder; mp 105–106.5 °C (toluene). 1H NMR (400 MHz,
CDCl3): d = 0.91 (t, 3 H, J = 7.2 Hz, CH3CH2O), 4.03 (q, 2
H, J = 7.2 Hz, CH3CH2O), 6.08 (br s, 2 H, NH2), 6.11 (s, 1
H, thiophene-CH), 7.45 (dd, 1 H, J = 8.4, 8.4 Hz, ArH), 7.62
(ddd, 1 H, J = 8.4, 1.2, 1.2 Hz, ArH), 8.12 (ddd, 1 H, J = 8.4,
1.2, 1.2 Hz, ArH), 8.16 (dd, 1 H, J = 1.2, 1.2 Hz, ArH). 13
C
NMR (400 MHz, CDCl3): d = 13.56 (q), 59.51 (t), 105.14
(s), 106.67 (d), 121.57 (d), 123.96 (d), 127.92 (d), 134.96
(d), 138.77 (s), 139.87 (s), 147.35 (s), 164.36 (s), 165.04 (s).
HRMS: m/z calcd for C13H12N2O4S [M+]: 292.0518; found:
292.0519.
Compound 2e: Purified by method A (CHCl3); yield: 52%;
white powder; mp 126–127 °C (EtOH). 1H NMR (400 MHz,
CDCl3): d = 0.94 (t, 3 H, J = 7.2 Hz, CH3CH2O), 4.03 (q, 2
H, J = 7.2 Hz, CH3CH2O), 6.04 (br s, 2 H, NH2), 6.06 (s, 1
H, thiophene-CH), 7.39 (ddd, 1 H, J = 8.4, 8.4, 0.6 Hz, ArH),
7.51 (ddd, 1 H, J = 8.4, 1.2, 1.2 Hz, ArH), 7.56 (ddd, 1 H,
J = 8.4, 1.2, 1.2 Hz, ArH), 7.59 (ddd, 1 H, J = 1.2, 1.2, 0.6
Hz, ArH). 13C NMR (400 MHz, CDCl3): d = 13.59 (q), 59.46
(t), 105.27 (s), 106.42 (d), 111.29 (s), 118.74 (s), 127.93 (d),
130.18 (d), 132.54 (d), 133.31 (d), 138.96 (s), 139.59 (s),
164.28 (s), 165.04 (s). HRMS: m/z calcd for C14H12N2O2S
[M+]: 272.0619; found: 272.0621.
Compound 2f: Purified by method A (CH2Cl2–hexane, 1:2);
yield: 64%; white powder; mp 102–103 °C (hexane). 1H
NMR (400 MHz, CDCl3): d = 0.89 (t, 3 H, J = 7.2 Hz,
CH3CH2O), 1.37 (t, 3 H, J = 7.1 Hz, CH3CH2O), 4.01 (q, 2
H, J = 7.2 Hz, CH3CH2O), 4.36 (q, 2 H, J = 7.1 Hz,
CH3CH2O), 5.95 (br s, 2 H, NH2), 6.07 (s, 1 H, thiophene-
CH), 7.36 (dd, 1 H, J = 7.6, 7.6 Hz, ArH), 7.47 (ddd, 1 H,
J = 7.6, 1.0, 1.0 Hz, ArH), 7.97 (ddd, 1 H, J = 7.6, 1.0, 1.0
Hz, ArH), 7.98 (dd, 1 H, J = 1.0, 1.0 Hz, ArH). 13C NMR
(400 MHz, CDCl3): d = 13.53 (q), 14.20 (q), 59.36 (t), 60.75
(t), 104.67 (s), 105.89 (d), 127.12 (d), 127.89 (d), 129.57 (s),
130.06 (d), 133.26 (d), 138.58 (s), 140.47 (s), 163.99 (s),
165.45 (s), 166.45 (s). HRMS: m/z calcd for C16H17NO4S
[M+]: 319.0878; found: 319.0869.
(18) Heterocyclization; Typical Conditions: A 25-mL round-
bottomed two-necked flask equipped with a magnetic
stirring bar and argon inlet tube was charged with
acetophenone (2.40 g, 20.0 mmol), ethyl cyanoacetate (3.39
g, 30.0 mmol), 95% EtOH (5 mL), morpholine (2.61 g, 30.0
mmol), and glacial AcOH (0.60 g, 10 mmol). The mixture
was stirred at 55 °C (temperature of bath) for 3 h. Finely
powdered sulfur (3 × 0.32 g, 10 mmol) was then added in
equal portions. After addition of each new portion the
mixture was flushed with argon and left stirring at 55 °C for
10–12 h (overall reaction time 36–40 h). The mixture was
transferred to a separating funnel containing CH2Cl2 (30
mL) and H2O (30 mL). The organic layer was separated,
washed with brine (4 × 10 mL), filtered through a short plug
of silica, and concentrated in vacuo to give 4.62 g of the
crude product. 1H NMR spectroscopy indicated 92%
conversion of acetophenone to 2a.
Purification; Method A: Column chromatography (silica
gel; CHCl3) gave 2a (3.38 g, 68%); off-white plates; mp 98–
99 °C (hexane, Lit.1b mp 98 °C).
Method B: The crude product was dissolved in EtOAc (10
mL), and a solution of anhyd HCl (2.2 M) in anhyd EtOAc
(15 mL, 33 mmol of HCl) was added to furnish a resinous
cake. The cake was thoroughly triturated until crystallization
began. The mixture was allowed to stand in a refrigerator
overnight. The crystalline hydrochloride was collected by
filtration, then washed with EtOAc (3 × 3 mL), and dried in
air to give 3.92 g of crude hydrochloride. The residue was
suspended in 5% aq NH3 (10 mL) in CH2Cl2 (20 mL). The
Synlett 2006, No. 16, 2559–2564 © Thieme Stuttgart · New York