Tetrahedron Letters
Titanium isopropoxide/pyridine mediated Knoevenagel reactions
⇑
Brian A. Robichaud, Kevin G. Liu
Chemical & Pharmacokinetic Sciences, Lundbeck Research, Paramus, NJ 07652, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a Ti(OiPr)4/pyridine mediated Knoevenagel reaction between aromatic ketones and cyanoac-
etamides to provide Knoevenagel olefin products in good to excellent yields. Almost in all cases studied, a
single geometrical isomer was formed and isolated under the Ti(OiPr)4/pyridine condensation conditions.
This methodology was also demonstrated to be highly effective between some other Knoevenagel active
methylene compounds and aromatic ketones.
Received 22 August 2011
Revised 12 October 2011
Accepted 12 October 2011
Available online 20 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Knoevenagel reaction
Knoevenagel condensation
Titanium isopropoxide
2-Aminothiophenes
Thiophenes
Recently, as part of our medicinal chemistry efforts in developing
therapeutic agents for central nervous system (CNS) diseases, we
desired the multifunctionalized 2-aminothiophene 1 (Scheme 1)
as a key intermediate to synthesize derivatives for structure–
activity relationship (SAR) studies. The classical synthesis for 2-ami-
nothiophenes is through Gewald reaction which typically involves a
ketone or aldehyde, a methylene active nitrile, elemental sulfur, and
an amine.1,2 However, in the case of 1, this classical reaction pro-
vided essentially no product under a variety of reaction conditions.
Upon close examination, we found that the olefin 4, which is the
presumed intermediate for the Gewald product 1, was not formed
under the reaction conditions. An efficient two-step synthesis for
aminothiophene 1 through olefin 4 was desired and is the subject
of this report.
The Knoevenagel reaction was discovered more than a century
ago and covers a variety of condensations typically between an
aldehyde or a ketone and an active methylene compound in the
presence of a weak base to provide olefin derivatives.3,4 While the
reaction in general works well with aldehydes, ketones, especially
aromatic ketones, which are much less reactive do not condense
well. It was not surprising that condensation between 2 and 3 under
standard Knoevenagel reaction conditions did not proceed (entries
1 and 2, Table 1). Much to our disappointment, the Lehnert modifi-
cation (TiCl4/base)5,6 which has been successfully used for certain
ketones and less reactive aldehydes also failed in this case (entry
3, Table 1). Ti(OiPr)4 is a good Lewis acid and an excellent dehydrat-
ing agent and has been used liberally for a variety of otherwise
challenging condensations such as formations of urea imines7 and
sulfinimines.8 To the best of our knowledge, this reagent has not
been well studied for Knoevenagel reactions. The only report about
Ti(OiPr)4 in context of the Knoevenagel reaction is its catalyzed
reactions between malononitrile and several aldehydes.9 This
prompted us to investigate its utility in the Knoevenagel reaction,
specifically those with challenging starting components.
Condensation of 2 and 3 with 1 equiv of Ti(OiPr)4 and 1 equiv of
pyridine in THF at room temperature (rt) for 15 h provided the
desired product 4 with 36% conversion as determined by LC–MS
(entry 4, Table 1). The conversion improved dramatically with
additional equivalents of Ti(OiPr)4 (entries 5 and 6, Table 1). In
the absence of pyridine (entry 8, Table 1) the reaction was signifi-
cantly slower indicating that pyridine plays an important role in
promoting the condensation. The optimal conditions identified
O
S8
O
(Gewald reaction)
N
H
+
O
N
H
NH2
N
3
2
S
1
O
NH
S8
N
4
⇑
Corresponding author.
Scheme 1. Geward and 2-step synthesis of thiophenes.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.