Efficient synthesis of N,N-disubstituted 5-aminothiophene-2-carboxaldehydes by nucleophilic aromatic substitution in water

Article abstract of DOI:10.1055/s-1998-1657

We have developed the first synthesis of N,N-disubstituted 5-aminothiophene-2-carboxaldehydes by Nucleophilic Aromatic Substitution of 5-bromothiophene-2-carboxaldehyde in water. This study shows selectivity between primary and secondary amines leading to

Full text of DOI:10.1055/s-1998-1657

April 1998
SYNLETT
383
Efficient Synthesis of N,N-Disubstituted 5-Aminothiophene-2-carboxaldehydes by
Nucleophilic Aromatic Substitution in Water
a
a
b
Damien Prim , Gilbert Kirsch and Jean-François Nicoud
a
Groupe de Synthèse Organique et Hétérocyclique, Laboratoire de Chimie Organique, Université de Metz, Ile du Saulcy, F-57045 Metz Cedex,
France. Fax: Int-33 3 87 31 53 33; email: prim@sciences.univ-metz.fr
b
Groupe des Matériaux Organiques, Institut de Physique et Chimie des Matériaux de Strasbourg, Université Louis Pasteur et CNRS (UM 046), 23,
rue du Loess, F-67037 Strasbourg Cedex, France
Received 19 January 1998
Abstract: We have developed the first synthesis of N,N-disubstituted 5-
aminothiophene-2-carboxaldehydes
by
Nucleophilic
Aromatic
Substitution of 5-bromothiophene-2-carboxaldehyde in water. This
study shows selectivity between primary and secondary amines leading
to the corresponding imines or amino derivatives respectively.
Since 1934 when Steinkopf reported the formation of colored reaction
1
intermediates by reacting nitrothiophene with nucleophiles ,
Nucleophilic Aromatic Substitution (SNAr) at the thiophene ring has
Scheme 1
2-21
received much attention
and is an attractive method for introducing
3-9
8,14, 21
6,8,14-18
nucleophiles such as alkoxy , alkylthio
at the thiophene ring.
or amino
groups
In these SNAr reactions, the thiophene nucleus is generally substituted
3,6,16-18
by one electron withdrawing group like nitro
or by a
combination of a nitro group and other electron attracting functions like
7,9
7,19
14,16,19
8,14,19
nitro , cyano , carboxylate
, acetyl
Leaving
, trifluoromethane-
4
14,19
sulfinyl ,
carboxamido.
groups
but also phenylsulfonyl
are
usually
17,18
4,5,8,14,15,18
7,15,16
halides
or methoxy
or
17,18
nitrophenoxy.
The solvents used in these studies are benzene,
toluene, xylene, methanol, dimethylsulfoxide, dimethylformamide or
acetonitrile.
To our knowledge, only a few examples of SNAr on 5-bromothiophene-
2-carboxaldehyde 1 by neutral nucleophiles have been reported. One by
using a mixture of dimethyl (or diethyl) amine, dimethyl (or diethyl)
ammonium bromide in methanol (or ethanol) followed by the hydrolysis
22
of the intermediate imminium salt in basic media , others by refluxing
23
the thiophene derivative with dibutylamine in xylene and piperidine in
24
DMSO. These preparations afford 52, 49 and 81% respectively of the
corresponding amino derivatives.
Indeed, polar solvents are useful in SNAr reactions but water, which is
25
already used in various classes of reactions , to our knowledge has not
been used so far in such reactions.
On the other hand, 5-dialkylamino-thiophene-2-carboxaldehydes have
been
obtained
through
electrophilic
substitution
on
26
dialkylaminothiophenes.
The reaction could be extended to various secondary amines (entries
We describe here an easy, one step and high yielding access to various
N,N-dialkyl and N,N-alkylarylaminothiophene-2-carboxaldehydes from
the mildly activated 5-bromothiophene-2-carboxaldehyde 1 using water
as a solvent.
6-16), allowing the formation of 5-aminothiophene-2-carboxaldehydes
2 in high yields under simple reaction conditions (Table 1). The low
yield obtained for compound 2g (entry 11) can be explained by
difficulties of removal of dibutylamine at the purification step.
Reactions with diphenylamine and N-methylaniline (entries 12-15) did
not lead to the desired aminothiophenes, probably due to the low
nucleophilicity of these amines.
Refluxing thiophene 1 in water with one equivalent of morpholine
furnished the desired amino derivative 2a in 38% yield (Table 1, entry
1). Increasing the amount of amine (2 or 3 equiv.) yielded 62 and 94%
of substituted product respectively (entries 2, 3). These first experiments
showed the feasibility of SNAr reactions in water on 5-bromothiophene-
2-carboxaldehyde 1, even mildly activated by a carboxaldehyde group
(Scheme 1). The use of only 1.1 equivalent of the reacting amine is also
possible without decrease of the yield (entries 4, 5) by adding 2
equivalents of a neutral base such as tributyl- or triethylamine. These
experiments show that the reaction needs an excess of base to succeed.
Using the more nucleophilic N-methyl para-anisidine, gave the N-[5-(4-
methoxyphenyl)]-N-methylaminothiophene-2-carboxaldehyde 2j in
66% yield. In comparison to other aminations by SNAr in the thiophene
22-24
series
, the higher yields which we describe here can be explained
by a better solubilization and stabilization of the polar transition states
27
in the water-amine mixture . The actual role of water will be further
investigated in an ongoing mechanistic study. The selectivity of the
reaction with secondary amine was shown by reacting under the same

384
LETTERS
SYNLETT
conditions a primary amine which only led to the formation of the imine
17) Spinelli, D.; Consiglio, G.; Noto, R. J. Org. Chem. 1978, 43,
3 (Scheme 1).
4038.
18) Spinelli, D.; Consiglio, G.; Noto, R. J. Heterocycl. Chem. 1977,
14, 1325.
In summary, we succeeded in the preparation of several N,N-
disubstituted 5-aminothiophene-2-carboxaldehydes in high yield, one
pot process using water as a solvent . Selectivity of primary towards
secondary amines has also been shown.
19) Dell'Erba, C.; Sancassan, F.; Novi, M.; Spinelli, D.; Consiglio, G.;
28
Arnone, C.; Ferroni, F. J. Chem. Soc., Perkin Trans. 2 1989, 1779.
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C.; Leandri, G.; Terrier, F. Gazz. Chim. Ital. 1987, 117, 267.
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Steinkopf, W.; Jacob, H. Justus Liebigs Ann. Chem. 1934, 513,
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5)
6)
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28) Typical procedure for the SNAr of 1 with secondary amines in
water: to 1 (0.38g, 2 mmol) and 4-hydroxy piperidine (0.6g, 6
mmol) were added 10ml of water. The resulting mixture was
stirred overnight at reflux. The reaction flask was allowed to cool
down to room temperature. The precipitate was filtrated and
washed twice with water. The crude product was purified by
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chromatography on silica gel (CH Cl / AcOEt 1:1) to furnish 2e.
2
2
12) Arnone, C.; Consiglio, G.; Frenna, V.; Mezzina, E.; Spinelli, D.
-1
2e: m.p. 142°C; IR (KBr) cm : 1608. UV/Vis (MeOH) nm (ε):
Heterocycles 1994, 37, 1529.
1
371 (25200). H NMR (250 MHz, CDCl ) δ 1.72(m, 2H, CH ),
3
2
13) Dell'Erba, C.; Spinelli, D. Tetrahedron 1965, 21, 1061.
1.98(m, 2H, CH ), 2.65(brs, 1H, OH), 3.21(m, 2H, CH ), 3.63 (m,
2
2
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2H, CH ), 3.97 (m, 1H, CH), 6.08 (d, 1H, H , J = 4.35Hz), 7.47
2
4
13
(d, 1H, H , J = 4.35Hz), 9.46 (s, 1H, CHO). C NMR (CDCl ) δ
3
3
15) Arnone, C.; Consiglio, G.; Frenna, V.; Mezzina, E.; Spinelli, D.
180.4 (CHO), 167.9 (C ), 140.1 (C ), 126.8 (C ), 104.5 (C ), 65.9
5
3
2
4
J. Chem. Res.(S) 1993, 440; (M) 1993, 2949.
(CHOH), 47.3 (NCH ), 32.8(CH ). Elemental analysis: Calcd for
2
2
16) Consiglio, G.; Arnone, C.; Spinelli, D.; Noto, R. J. Chem. Soc.,
Perkin Trans. 2 1981, 642.
C H O NS: C:56.85, H: 6.20, N: 6.63; Found: C: 56.97, H:
10 13 2
6.19, N: 6.81.