192
Chemistry Letters 2001
A New Ring-Forming Methodology for the Synthesis of
Conformationally Constrained Bioactive Molecules
Demetris P. Papahatjis,* Spyros Nikas, Andrew Tsotinis,† Margarita Vlachou,† and Alexandros Makriyannis††
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation,
48 Vas. Constantinou Ave., Athens 116 35, GREECE
†University of Athens, School of Pharmacy, Department of Pharmaceutical Chemistry,
Panepistimiopolis-Zografou, GR-157 71, Athens, GREECE
††Departments of Pharmaceutical Sciences and Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, U.S.A.
(Received December 12, 2000; CL-001115)
A new, general, one pot method for introducing carbocyclic
rings alpha to a nitrile moiety is described. Treatment of readily
available arylacetonitriles with potassium bis(trimethylsilyl)-
amide and subsequent alkylation with α,ω-dibromo or dichloro-
alkanes in tetrahydrofuran under anhydrous conditions at 0 °C
produces cycloalkyl adducts in good yields and short reaction
times.
aldehydes have, therefore, been utilized in order to achieve
these transformations.
A typical example of this approach is the cyclobisalkylation
of activated oxazine derivatives, which upon reduction and sub-
sequent hydrolysis give the desired α,α-cyclobisalkylated alde-
hydes.5 More recently, the construction of cycloalkyl rings at
the α-position of aldehydes by cyclization of ω-haloaldimines
was described. This method involves alkylation of the corre-
sponding aldimines with α,ω-dihaloalkanes followed by treat-
ment with LDA to give α,α-cyclobisalkyl aldimines which are
then hydrolyzed to the α,α-cycloalkylaldehydes.4 However, all
of these literature methods are generally not very efficient and
give relatively low yields.
We now report a new, general, one pot method for the con-
struction of carbocyclic rings alpha to the nitrile moiety which
serves as a masked aldehyde. As shown in Scheme 1, our
approach is simple, highly efficient and also suitable for the
preparation of strained rings. After considerable experimenta-
tion we found that when readily available 3,5-dimethoxy-
phenylacetonitrile in dry tetrahydrofuran (0.1 M), was deproto-
nated with potassium bis(trimethylsilyl)amide (3 equiv) at 0 °C
under an argon atmosphere and subsequently alkylated at the
same temperature with α,ω-dibromo or dichloroalkanes (1.1
equiv) the cycloalkyl adducts 3–6 were formed in 58–94%
yield. The reaction is simple to carry out and is usually com-
plete in 20–25 min.
The biological activity and stability of bioactive molecules
are frequently enhanced when such molecules are subjected to
conformational constraint.1 Previously, we and others, have
published2,3 the synthesis of molecules of biological interest
bearing conformationally constrained side chains. In the course
of our program directed towards the synthesis of conformation-
ally constrained (–)-∆8-tetrahydrocannabinol and melatonin
analogs, we were faced with the problem of introducing cyclo-
propane, cyclobutane, cyclopentane and cyclohexane rings at
the α-position of nitriles of type 1 and 2 (Figure 1).
This has motivated us to develop a general method for sub-
stituting activated aryl methylenes with cycloalkyl groups of
varying ring size. Cyclobisalkylation reactions are especially
valuable when the resulting rings bear functional groups that
can be further elaborated to target molecules. In the specific
case of α,α-cycloalkylaldehyde synthesis, several methods have
been reported including alkylation of enolates derived from
aldehydes with α,ω-dihaloalkanes. However, this approach
usually leads to complex mixtures often without the formation
of the desired cycloalkane carboxaldehydes.4 Masked forms of
In order to explore the versatility of our method we applied
it to the construction of the 3-indolylcycloalkane analogs 11–18
(Table 1), which, like their phenolic counterparts, 3–6, were
obtained in good yields. Table 1 includes examples of carbo-
cyclic rings synthesized according to the above method and
Copyright © 2001 The Chemical Society of Japan
Papahatjis, Demetris P.
