First synthesis of 3-acetyl-2-aminothiophenes using the gewald reaction

Article abstract of DOI:10.3390/11050371

Novel 3-acetyl-2-aminothiophenes were prepared from cyanoacetone and 1,4-dithianyl-2,5-diols using a modified Gewald reaction. The syntheses of the corresponding acetamides, as well as that of 3-acetyl-2-amino-5-nitrothiophene - an interesting building-block for thiophene azo dyes - are reported. Detailed spectroscopic investigations (1H-NMR, ¹³C-NMR, MS, IR) of the obtained compounds are presented.

Full text of DOI:10.3390/11050371

Molecules 2006, 11, 371-376
molecules
ISSN 1420-3049
http://www.mdpi.org
Short Paper
First Synthesis of 3-Acetyl-2-aminothiophenes Using the Gewald
Reaction
Gernot A. Eller * and Wolfgang Holzer †
Department of Drug Synthesis, Faculty of Life Sciences, University of Vienna, Austria; † E-Mail:
wolfgang.holzer@univie.ac.at
* Author to whom correspondence should be addressed. E-mail: gernot.eller@univie.ac.at
Received: 5 May 2006; in revised form: 15 May 2006 / Accepted: 16 May 2006 / Published: 16 May
2006
Abstract: Novel 3-acetyl-2-aminothiophenes were prepared from cyanoacetone and
1,4-dithianyl-2,5-diols using a modified Gewald reaction. The syntheses of the
corresponding acetamides, as well as that of 3-acetyl-2-amino-5-nitrothiophene – an
interesting building-block for thiophene azo dyes – are reported. Detailed spectroscopic
investigations (1H-NMR, 13C-NMR, MS, IR) of the obtained compounds are presented.
Keywords: Gewald reaction; Thiophene synthesis; Cyclization; Condensation.
Introduction
Various substituted and fused 2-aminothiophenes have attracted considerable attention as structural
motifs in numerous pharmaceuticals and dyes, whereof the tranquillizer brotizolam (Lendormin®),
containing a thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine moiety, represents the best-known of
such derivatives [1–3]. Although several thiophene ring syntheses are known in the literature [1] for
the synthesis of thiophen-2-amines, the subsequent introduction of the amino group into an existing
thiophene moiety is difficult and thus remains a challenging task. In contrast, during the classical
Gewald thiophene synthesis – the reaction of an activated nitrile with an α-mercaptoaldehyde or with
an α-mercaptoketone – an amino function is introduced right at the 2 position and therefore this
reaction proves to be second to none for the construction of an 2-aminothiophene moiety (Scheme 1)
[4].

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372
Scheme 1. The classical Gewald thiophene synthesis.
X
Y
SH
N
Z
X
Y
S
NH2
Z
base
+
O
Z = COOR, CN, CONH2, COAryl
Activated nitriles used so far in the Gewald reaction are cyanoacetic acid esters, malonodinitrile,
cyanoacetohydrazides and benzoylacetonitrile, which lead to the corresponding 3-alkoxycarbonyl-,
3-cyano-, 3-carbamoyl-, and 3-benzoylthiophen-2-amines, respectively [5]. To the best of our
knowledge, however, the use of cyanoacetone for this purpose has not been reported yet. In this regard
we now report an extension to the reaction's scope for the synthesis of 3-acetyl-2-aminothiophenes that
are foreseen to be interesting building blocks.
Results and Discussion
In a modified Gewald reaction the labile cyanoacetone (2) – easily accessible from its
commercially available sodium salt 1 – was cyclized with the appropriate α-mercaptoaldehyde dimers
3 using triethylamine in DMF at 60 °C to afford the novel 3-acetyl-2 aminothiophenes 4, moderately
stable at room temperature. Subsequent heating with acetic anhydride gave the stable acetamides 5
(Scheme 2).
Scheme 2. Synthesis of the title compounds 4 and the corresponding acetamides 5.
O
O
3–5
a
b
R
H
Me
HCl/H2O
CH2Cl2
N
N
Me
HO
Me
Na
1
2
R
S
S
OH
S
NH2
Ac
S
NHAc
Ac
Ac2O
2
DMF, NEt3,
60 °C
R
R
R
3a,b
4a,b
5a,b
One potential practical application of acetamides 5 was realized in the synthesis of the azo-dye
building-block 7. It is well-known that related 3-alkoxycarbonyl and 3-cyanothiophenyl-2-amines
containing an unsubstituted 5 position in the thiophene ring are labile compounds which undergo
unwanted dimerization upon attempted diazotization [6]. However, this problem can be circumvented
by 'blocking' this activated 5-position with a nitro group [7]. According to this strategy, compound 5a
was transformed into the corresponding 5-nitro derivative 6, which after acidic hydrolysis gave the

Molecules 2006, 11
373
nitrothiophenamine 7. This deeply yellow colored compound has already been used in azo-couplings
but neither its synthesis nor any analytical data have been reported so far [8].
Scheme 3. Preparation of the thiophene azo-dye building block 7.
S
NHAc
Ac
O2N
S
NHAc
Ac
O2N
S
NH2
Ac
HNO3
HCl / H2O
EtOH
H2SO4
5a
6
7
Conclusions
A variation of the Gewald thiophene synthesis was developed to yield novel 3-acetyl-
2-aminothiophenes. Nevertheless, the possibility of adapting this new procedure to other
3-oxoalkanenitriles and other 1,4-dithianes of type 3 that are not yet commercially available requires
further investigation.
Experimental Section
General
Melting points were determined on a Reichert–Kofler hot-stage microscope and are uncorrected.
Mass spectra were obtained on a Shimadzu QP 1000 instrument (EI, 70 eV). IR spectra were recorded
on a Perkin-Elmer FTIR 1605 spectrophotometer. Elemental analyses were performed at the
Microanalytical Laboratory at the University of Vienna. 1H- and 13C-NMR spectra were recorded on a
1
13
Varian UnityPlus 300 spectrometer (299.95 MHz for H, 75.43 MHz for C) at 28 °C. The centre of
the solvent signal was used as an internal standard which was related to TMS with δ = 7.26 ppm (1H in
CDCl3), δ = 2.49 ppm (1H in DMSO-d6), δ = 77.0 ppm (13C in CDCl3), and δ = 39.5 ppm (13C in
DMSO-d6). All reagents and solvents were purchased from Sigma-Aldrich, except compounds 1, 3a,
and 3b, which were obtained from Merck, Fluka, and Oakwood Products, respectively.
3-Oxobutanenitrile (2) [9]
To a solution of cyanoacetone sodium salt (1, 5.25 g, 50 mmol) in water (150 mL) was added
CH2Cl2 (100 mL). Whilst stirring, the mixture was adjusted to pH 1 with conc. HCl. The organic layer
was separated, the aqueous layer was extracted once again with CH2Cl2 (100 mL) and the combined
organic layers were dried over anhydrous Na2SO4. While keeping the bath temperature below 30 °C,
the solvent was removed under reduced pressure to afford 2 (3.60 g, 87%) as a colorless and unstable
1
oil (pure according to H-NMR), which was used immediately and without further purification in the
next reaction step. 1H-NMR [10] (CDCl3): δ = 2.34 (s, 3H, CH3), 3.48 (s, 2H, CH2); 13C-NMR (CDCl3):
1
1
2
δ = 29.2 (CH3, J = 128.9 Hz), 32.7 (CH2, J = 128.9 Hz, J(CH2,CH3) = 1.8 Hz), 113.7 (CN,
2J(CN,CH2) = 9.7 Hz), 195.0 (CO, 2J(CO,CH2) = 6.4 Hz, 2J(CO,CH3) = 6.4 Hz).

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1-(2-Amino-3-thienyl)ethanone (4a)
Triethylamine (1 g, 10 mmol) was added with stirring to a solution of crude 2 (3.60 g, 43 mmol)
and dithiane 3a (3.35 g, 22 mmol) in DMF (10 mL), whereupon the temperature of the solution rose
slightly. After 15 min, the solution was heated to 60 °C for 3 h. Then, the solvent was removed under
reduced pressure and H2O (50 mL), diethyl ether (50 mL), and glacial acetic acid (ca. 1–3 mL) were
added to the oily residue until the organic layer became clear. After separation of the ethereal layer and
further extraction of the aqueous layer with diethyl ether (50 mL), the combined organic layers were
washed subsequently with 5% aqueous NaHCO3 and H2O, dried over anhydrous Na2SO4 and
evaporated under reduced pressure to afford 4a (3.98 g, 65%) as a yellow, slowly darkening oil, which
1
was pure according to TLC and H-NMR. B.p.: 148 °C (7 mbar); IR (KBr): 3382, 3283, 1616, 1589
1
3
cm-1; H-NMR (CDCl3): δ = 2.38 (s, 1H, CH3), 6.12 (d, J(H5,H4) = 5.8 Hz, 1H, H5), 6.84 (s, 2H,
NH2), 6.91 (d, 3J(H5,H4) = 5.8 Hz, 1H, H4); 13C-NMR (CDCl3): δ = 28.1 (CH3, 1J = 127.1 Hz), 106.3
1
2
3
3
(C5, J = 190.5 Hz, J(C5,H4) = 5.6 Hz), 115.8 (C3, J(C3,H5) = 8.6 Hz, J(C3,H4) = 6.0 Hz,
3J(C3,CH3) = 1.4 Hz), 125.9 (C4, 1J = 166.6 Hz, 2J(C4,H5) = 3.9 Hz), 164.2 (C2, 3J(C2,H4) = 10.2 Hz,
3J(C2,H5) = 6.5 Hz), 193.8 (CO, J(CO,CH3) = 5.8 Hz); MS m/z (%) = 141 (M+, 66), 126 (100), 98
2
(17); HRMS m/z calcd. for C6H7NOS: 141.0248. Found: 141.0251.
1-(2-Amino-4-methyl-3-thienyl)ethanone (4b)
Triethylamine (1 g, 10 mmol) was added with stirring to a solution of crude 2 (2.08 g, 25 mmol)
and dithiane 3b (2.25 g, 12.5 mmol) in DMF (10 mL) and the mixture was heated to 60 °C for 5 h.
Then, the solvent was removed under reduced pressure and the semi-solid residue was recrystallized
from cyclohexane–CH2Cl2 to afford 1.63 g (41%) of 4b as yellowish to brownish crystals. M.p.: 145–
1
4
148 °C; IR (KBr): 3332, 3228, 3127, 1602, 1575 cm–1; H-NMR (CDCl3): δ = 2.34 (d, J(CH3,H5) =
4
1.2 Hz, 3H, CH3), 2.44 (s, 3H, COCH3), 5.97 (q, J(H5,CH3) = 1.2 Hz, 1H, H5), 7.00 (s, 2H, NH2);
13C-NMR (CDCl3): δ = 19.6 (CH3, 1J = 127.8 Hz, 3J(CH3,H5) = 4.0 Hz), 30.6 (COCH3, 1J = 127.2 Hz),
1
3
2
103.2 (C5, J = 187.7 Hz, J(C5,CH3) = 7.1 Hz), 116.0 (C3), 134.7 (C4, J(C4,CH3) = 6.3 Hz,
2J(C4,H5) = 3.4 Hz), 166.3 (C2, 3J(C2,H5) = 6.8 Hz), 194.5 (CO, 2J(CO,CH3) = 5.8 Hz); MS m/z (%)
= 155 (M+, 84), 140 (100); Anal. calcd. for C7H9NOS · 0.1 H2O: C, 53.54; H, 5.91; N, 8.92. Found: C,
53.52; H, 5.57; N, 8.67.
N-(3-Acetyl-2-thienyl)acetamide (5a)
Thiophenamine 4a (1.41 g, 10 mmol) and excess acetic anhydride (5 mL) were refluxed for 15 min.
Then, H2O (ca. 10 mL) was added and the mixture was heated again for a further 5 min. Upon cooling
overnight, the product crystallized as slightly yellowish needles. Concentration of the mother liquor
gave additional crystals. In total 1.74 g (95%) of 5a were obtained. M.p.: 92–94 °C; IR (KBr): 1683,
1635 cm–1; 1H-NMR (CDCl3): δ = 2.29 (s, 3H, NCOCH3), 2.52 (s, 3H, COCH3), 6.72 (d, 3J(H5,H4) =
3
13
5.8 Hz, 1H, H5), 7.18 (d, J(H4,H5) = 5.8 Hz, 1H, H4), 11.88 (s, 1H, NH); C-NMR (CDCl3): δ =
23.5 (NCOCH3, 1J = 129.0 Hz), 28.7 (COCH3, 1J = 127.7 Hz), 116.0 (C5, 1J = 187.0 Hz, 2J(C5,H4) =
1
2
5.0 Hz), 120.8 (C3), 124.1 (C4, J = 168.3 Hz, J(C4,H5) = 3.6 Hz), 149.4 (C2), 167.7 (NCO,
2J(NCO,NH) = 6.4 Hz, J(NCO,NCOCH3) = 4.6 Hz), 195.8 (CO, J(CO,COCH3) = 5.8 Hz); MS m/z
2
2

Molecules 2006, 11
375
(%) = 183 (M+, 18), 141 (68), 126 (100); Anal. calcd. for C8H9NO2S: C, 52.44; H, 4.95; N, 7.64.
Found: C, 52.37; H, 4.74; N, 7.54.
N-(3-Acetyl-4-methyl-2-thienyl)acetamide (5b)
Applying a procedure similar to that used for the synthesis of acetamide 5a, 0.91 g (92%) of 5b
were obtained as almost colorless needles starting from 4b (0.78 g, 5 mmol) and excess acetic
anhydride (3 mL). M.p.: 128–132 °C; IR (KBr): 1676, 1619 cm–1; 1H-NMR (CDCl3): δ = 2.26 (s, 3H,
3
3
NCOCH3), 2.45 (d, J(CH3,H5) = 1.2 Hz, 3H, CH3), 2.54 (s, 3H, COCH3), 6.38 (q, J(H5,CH3) = 1.2
13
1
3
Hz, 1H, H5), 12.32 (s, 1H, NH); C-NMR (CDCl3): δ = 19.1 (CH3, J = 128.0 Hz, J(CH3,H5) = 4.0
1
1
1
Hz), 23.8 (NCOCH3, J = 128.9 Hz), 31.3 (COCH3, J = 127.9 Hz), 113.9 (C5, J = 184.2 Hz,
3J(C5,CH3) = 6.6 Hz), 120.8 (C3), 133.2 (C4, J(C4,CH3) = 6.2 Hz, 2J(C4,H5) = 3.2 Hz), 151.7 (C2),
2
167.9 (NCO), 196.9 (CO); MS m/z (%) = 197 (M+, 32), 155 (66), 140 (100), 43 (71); Anal. calcd. for
C9H11NO2S: C, 54.80; H, 5.62; N, 7.10. Found: C, 54.52; H, 5.36; N, 7.19.
N-(3-Acetyl-5-nitro-2-thienyl)acetamide (6)
Acetamide 5b (1.37 g, 7.5 mmol) was added carefully over a period of 30 min at 0 °C to a well
stirred mixture of HNO3 (65%, 2.5 mL, d = 1.4 g/mL, 36 mmol) and H2SO4 (98%, 2.5 mL, d = 1.8
g/mL, 46 mmol). After the addition was complete, the deeply colored reaction mixture was stirred for
a further 10 min and was then poured cautiously into excess ice-water. The precipitate formed was
filtered off, washed with H2O, and dried under reduced pressure to afford 2.07 g (91%) of 6 (pure
1
according to H-NMR). An analytically pure sample was obtained by recrystallization from MeOH–
1
DMF. M.p.: 178–179 °C; IR (KBr): 3182, 3079, 1683, 1655 cm–1; H-NMR (DMSO-d6): δ = 2.36 (s,
3H, NCOCH3), 2.57 (s, 3H, COCH3), 8.55 (s, 1H, H4), 11.94 (s, 1H, NH); 13C-NMR (DMSO-d6): δ =
1
1
2
23.1 (NCOCH3, J = 129.7 Hz), 28.6 (COCH3, J = 128.3 Hz), 119.7 (C3, J(C3,H4) = 3.6 Hz,
3J(C3,NCOCH3) = 1.4 Hz), 129.2 (C4, J = 177.6 Hz), 139.8 (C2), 151.4 (C5, J(C5,H4) = 11.9 Hz),
170.2 (NCO, 2J(NCO,NCOCH3) = 6.7 Hz), 195.6 (CO, 2J(CO,COCH3) = 6.1 Hz, 3J(CO,H4) = 1.8 Hz);
MS m/z (%) = 228 (M+, 4), 186 (20), 69 (42), 43 (100); Anal. calcd. for C8H8N2O4S: C, 42.10; H, 3.53;
N, 12.27. Found: C, 42.11; H, 3.66; N, 12.16.
1
2
1-(2-Amino-5-nitro-3-thienyl)ethanone (7)
A mixture of nitroacetamide 6 (1.14 g, 5 mmol), EtOH (5 mL), and conc. HCl (15 mL) was
refluxed overnight (18 h). Removal of EtOH under reduced pressure and refrigeration of the reaction
mixture for 48 h produced a dark precipitate. The solid was filtered off, washed with water, and dried
under reduced pressure. The residue was treated three times with hot acetone (10 mL) and filtered. The
combined acetone phases were concentrated to almost dryness to afford pure 7 (0.66 g, 70%) as a dark
yellow powder. M.p.: 222–224 °C; 1H-NMR (DMSO-d6): δ = 2.40 (s, 3H, CH3), 8.28 (s, 1H, H4), 9.11
2
(s, 2H, NH2); 13C-NMR (DMSO-d6): δ = 27.80 (CH3, 1J = 127.7 Hz), 114.5 (C3, J(C3,H4) = 3.8 Hz,
3J(C3,CH3) = 1.5 Hz), 129.7 (C5), 133.4 (C4, 1J = 174.6 Hz), 168.3 (C2, 3J(C2,H4) = 12.1 Hz), 194.2
(CO, 2J(CO,CH3) = 5.8 Hz, 3J(CO,H4) = 1.8 Hz); MS m/z (%) = 186 (M+, 100), 69 (58); Anal. calcd.
for C6H6N2O3S: C, 38.70; H, 3.25; N, 15.05. Found: C, 38.95; H, 3.33; N, 14.80.

Molecules 2006, 11
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Sample Availability: Available from the authors.
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