Enamines in solid-phase: Synthesis and reactivity towards electrophiles

Article abstract of DOI:10.1016/S0040-4039(00)00946-1

Enamines are synthesized in solid-phase by amination of terminal, acetylenes with a secondary amine attached to Wang resin in a process catalyzed by mercury (II) acetate. The enamines obtained react with electrophiles such as isocyanates and nitroolefins to give rise to the expected addition products, which can be released from the resin by hydrolysis of the enamine under mild acidic conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00946-1

Tetrahedron Letters 41 (2000) 5683±5687
Enamines in solid-phase: synthesis and reactivity towards
electrophilesy
Fernando Aznar,* Carlos Valdes and Marõa-Paz Cabal
Â
Instituto de Quõmica Organometalica `Enrique Moles', Unidad Asociada al CSIC, Universidad de Oviedo,
Â
Oviedo 33071, Spain
Received 3 May 2000; accepted 7 June 2000
Abstract
Enamines are synthesized in solid-phase by amination of terminal acetylenes with a secondary amine attached
to Wang resin in a process catalyzed by mercury(II) acetate. The enamines obtained react with electrophiles such
as isocyanates and nitroole®ns to give rise to the expected addition products, which can be released from the resin
by hydrolysis of the enamine under mild acidic conditions. # 2000 Elsevier Science Ltd. All rights reserved.
The development of combinatorial chemistry as a tool for the discovery of new drugs and
biologically active molecules has promoted a spectacular growth in solid-phase organic
synthesis.1 Nowadays, solid-phase chemistry2 is not restricted to the classic peptide couplings, but
in fact has been extended to carbon±carbon bond-forming processes, such as ole®nation
reactions, organometallic carbon±carbon couplings or ring closing metathesis.3
Nevertheless, many reactions and synthetic strategies that are commonly done in solution
phase have yet to be applied to solid-phase synthesis. One typical example is the addition of an
enamine to a carbon electrophile, such as a carbonyl compound, an acylating agent, a nitroole®n,
which is a well documented method for the creation of carbon±carbon bonds in solution,4 and
could be an excellent starting point for the synthesis of libraries of organic compounds in solid-
phase. Moreover, by attaching the enamine to the resin via the amino group, the ®nal compound
could be cleanly released from the resin by treatment under mild acidic conditions to yield the
free compound having a ketone functionality (Scheme 1).
Scheme 1.
* Corresponding author. Tel: (34)985103454; fax: (34)985103446; e-mail: fag@sauron.quimica.uniovi.es
y
Dedicated to Prof. Jose Barluenga on the occasion of his 60th Birthday.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00946-1

5684
In contrast to the wide spread use of imines in solid-phase organic synthesis,5 to the best of our
knowledge, the only example of an enamine used in solid-phase organic chemistry was disclosed
by Hird et al. for 2-amino-1,3-dienes and their cycloaddition reactions.6 A possible explanation
could be the lack of a synthetic method for the synthesis of enamines that can be easily adapted to
solid-phase chemistry.
Enamines formally derived from methyl ketones can be easily prepared by the addition of
secondary amines to terminal acetylenes, in a process catalyzed by mercury salts.7 The usefulness
of this methodology has been explored in our group for the synthesis of 2-amino-1,3-butadienes
from conjugated enynes,8 and their synthetic applications in cycloaddition reactions.9
In this paper we describe the application of this methodology to the solid-phase synthesis of
enamines, and their subsequent reactions with selected electrophiles.
1. Results and discussion
We carried out our studies with the solid-supported amine 1, that is readily prepared by
reaction of 4-(bromomethyl)phenoxymethyl polystyrene (Wang Bromo polystyrene resin) and
benzylamine. In the initial experiments with phenylacetylene (R=Ph), the amination reaction
proceeded by treating the resin in CH2Cl2, with a solution of phenylacetylene, Hg(OAc)2 and
diisopropyl amine in CH2Cl2. Best results were obtained after 72 hours at room temperature. At
this point, treatment of the resin with a 10% tri¯uoroacetic acid solution in CH2Cl2 a€orded
acetophenone, providing evidence of the formation of enamine 3 (Scheme 2).
Scheme 2.
In order to study the scope of this reaction we tried di€erent terminal acetylenes. This time, we
did not isolate the corresponding methyl ketones, but instead we allowed resin 3 to react with
electrophiles. Thus, reaction of the enamine resin 3 with an aromatic isocyanide in CH2Cl2
followed by treatment with 5% TFA in wet CH2Cl2 provides ketoamide 4. Similarly, reaction of
the enamine resin 3 with nitroole®ns gives rise after the hydrolytic cleavage under the same
conditions to nitroketones 5 (Scheme 3, Table 1).
In both types of reactions the purities and overall yields of the processes range from moderate
1
to good (in some instances a small amount of methyl ketone was detected by H NMR). The
methodology appears to be applicable to neutral and electron rich aromatic acetylenes and
conjugated enynes{ (4g±i). However, no reaction product is isolated for aromatic acetylenes with
{
The reaction of 2-amino-1,3-butadienes with nitroole®ns was not attempted since it is well known that it a€ords a
mixture of cyclic and open chain compounds both in solution and in solid-phase.6

5685
Scheme 3.
Table 1
b-Ketoamides 4 and g-nitroketones 5 prepareda
electron withdrawing substituents (5h,i) and alkylsubstituted acetylenes (5j). In some examples the
insolubility of the intermediates gives rise to the ®nal compound with low yield and purity (4f).
In conclusion, we have presented a new method for the synthesis of enamines in solid-phase,
and some examples of their reactivity with typical electrophiles. Given the variety of electrophiles
that can react with enamines and the ready availability of aromatic acetylenes by Sonogashira
coupling10 or Corey±Fuchs reaction,11 we believe this method can be very useful as a starting
point for the preparation of libraries of organic compounds.

5686
2. Experimental procedure
2.1. Preparation of aminobenzyl Wang resin 1
To a suspension of commercial 4-(bromomethyl)phenoxymethyl polystyrene (loading 0.8±1.4
mMol/g) (4 mMol) in 25 mL of DMF was added benzylamine (20 mMol, 2.14 g) and the mixture
was shaken overnight. The solvent was removed by ®ltration and the resin was washed with DMF
(3Â50 mL) and CH2Cl2 (3Â50 mL) and dried under vacuum. Then the resin was transferred to a
round-bottomed ¯ask and swollen with 50 mL of benzene, the suspension was re¯uxed overnight
with a Dean±Stark apparatus and a re¯ux condenser, in order to remove any traces of water. The
solvent was removed by ®ltration and the resin was dried under vacuum and stored in a desiccator.
2.2. General procedure for the solid-phase synthesis of amides 4 and nitro derivatives 5
1. Amination reaction: To a suspension of mercury(II) acetate (180 mg, 0.6 mMol) in 3 mL of
dry THF was added the terminal acetylene (0.7 mMol) and the mixture was stirred for 10 min.
Then 0.24 ml (1.8 mMol) of dry diisopropyl amine was added and the stirring continued for 15
min. The solution was transferred to a suspension of aminobenzyl Wang resin 1 (0.2 mMol) in 2
mL of dry CH2Cl2. The mixture was shaken for 72 h at room temperature. The solution was
removed by ®ltration, and the resin was washed once with 10 mL of dry CH2Cl2.
2. Addition of the electrophile and hydrolysis of the enamineÐsynthesis of compounds 4 and 5: To
the resin swollen in 3 mL of dry CH2Cl2 was added a solution of the electrophile (1.8 mMol) in 3
mL of CH2Cl2). The mixture was shaken for 6 h and then the solution was removed from the
resin by ®ltration. The resin was washed with CH2Cl2 (3Â15 mL), THF (3Â15 mL), MeOH
(2Â10 mL) and CH2Cl2 (15 mL). A 10% solution of TFA in CH2Cl2 was added to the resulting
resin and the mixture was shaken for 20 min. The solution was ®ltered and the resin was washed
with additional CH2Cl2. The ®ltrates were combined and evaporated under reduced pressure. The
residue was treated with 4 mL of CH2Cl2 and charcoal and the solution was ®ltered through
Celite and concentrated under reduced pressure to a€ord either compound 4 or 5.
Acknowledgements
This research was supported by the Comision Interministerial de Ciencia y Tecnologõa
(CICYT) and European Commission (Fondos FEDER 1FD97-0632).
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5687
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