Gold-catalyzed cyclization of Baylis – Hillman adducts Derived from formyl-indoles

Gold-catalyzed cyclization of Baylis–Hillman adducts Derived from formyl-indoles Benito Alcaide,∗ Pedro Almendros,∗ Alejandro Escobar, Fernando Herrera, and Amparo Luna a Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Orgánica I, Unidad Asociada al CSIC, Facultad de Química, Universidad Complutense de Madrid, 28040 Madrid b Instituto de Química Orgánica General, IQOG-CSIC, Consejo Superior de Investigaciones Científicas, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain


INTRODUCTION
The use of gold salts has gained a lot of attention in the recent times because of their powerful soft Lewis acidic nature.Such a property allows gold catalysts to activate unsaturated functionalities such as alkynes, alkenes, and allenes, to create C-C bonds under extremely mild conditions. 1 On the other hand, Baylis-Hillman (BH) adducts are usually flexible and multifunctional products which can be easily transformed in a huge number of derivatives. 2wever, although many efforts have been made in these fields, the gold-catalyzed reactions using BH adducts derived from formyl-indoles as substrates constitute an unexplored field of noble metal catalysis.In connection with our current research interest in metal-catalyzed reactions, 3 we wish to report now details of the cyclization of indole-tethered BH adducts to cyclopenta [b]indoles, 4 which is carried out using gold catalysis.

RESULTS AND DISCUSSION
Starting substrates, BH adducts 1a-c, 2a, and 2b (Figure 1) required for our study were prepared through a DABCO-catalyzed reaction from methyl acrylate and the appropriate indolecarbaldehydes. 5 Indole-linked acrylate 1a was synthesized according to a literature procedure. 6ovel BH adducts 1b, 1c, 2a, and 2b were prepared using the above standard procedure with slight modifications.Initially, we started to evaluate the cyclization reaction by employing BH adduct 1a as model substrate.NH-Indole-tethered α-hydroxacrylate 1a has diverse reactive sites, at which at least three different transformations (C-cyclization versus O-cyclization versus N-cyclization) can take place.
Our catalyst screening led to the identification of AuCl 3 as the most suitable promoter.AuCl and Gagosz' catalyst [(Ph3P)AuNTf 2 ] were less effective for the tricycle formation.Our solvent screening led to the identification of 1,2-dichloroethane (DCE) as the most suitable solvent.It was found that AuCl 3 is an effective reagent for the room temperature carbocyclization of indole-linked acrylate 1a to afford the cyclopentene-fused indole 3a in 40% yield in a totally selective fashion.
Nicely, using deactivated silica gel during purification resulted in an increased 50% yield for adduct 3a (Scheme 1).Similarly, 1,4-dihydrocyclopenta [b]indoles 3b-d were selectively obtained in the presence of the gold salt (Scheme 1).The placement of a chlorine atom or a methoxy group at C5 position of the indole ring was tolerated in the presence of AuCl 3 , providing a handle for subsequent orthogonal reactivity.
Due to the fact that the C3-position of an indole is the most reactive site for electrophilic functionalization, 7 carbocyclization of indole-tethered alkenes to the C2 indole position is considerably less studied and is mainly restricted to 1,2-dienes. 8Fortunately, the gold-catalyzed reaction of indole-tethered α-hydroxacrylates 2 was also successful.As shown in Scheme 2, under gold(III) catalysis, the C3-C2 annulation products 4 were obtained, but in modest yields.catalytic species (Scheme 3).

CONCLUSIONS
In conclusion, we have developed a convenient methodology for the gold-catalyzed direct synthesis of dihydrocyclopenta [b]indoles from Baylis-Hillman adducts derived from formylindoles.A conceivable mechanism for the achievement of cyclopentene-fused indoles may imply a selective indole hydroarylation followed by dehydration.