Miguel Tomás

1,4-Cycloaddition of 1,3-diazabutadienes with enamines: an efficient route to the pyrimidine ring

Abstract [4+2] Cycloaddition reactions of 2-trimethylsilyloxy- and 2-trimethylsilylthio-1,3-diazabutadienes with enamines leading to pyrimidone derivatives are described.

Synthesis of Heterocycles from Azadienes

Publisher Summary Azadienes have become a useful tool for the construction of heterocyclic compounds. In the chapter, their application toward natural product synthesis through pericyclic processes is reviewed and their great potential in the field of the alkaloid chemistry is demonstrated. The chapter describes the utility of azadienes and 1,3-diazadienes in the synthesis of heterocycles of various ring sizes. The [4 + 2] cycloaddition reactions of azadienes are reviewed in the chapter, focusing on Diels–Alder cycloadditions processes. It also summarizes the cycloaddition reactions of heterocyclic azadienes. The chapter describes the chemistry of 2-azadienes directed for the preparation of five- to seven-membered heterocycles; the study of electronically neutral 2-azadienes is an important subject. The chemistry of diazadienes is focused in the chapter in the utility of 1, 3-diazadienes. The electrocyclic ring closure reactions of vinyl or aryl 2-azadienes (azatrienes) involving six electrons occur at moderate temperatures and, in this respect, several pyridine syntheses are described in the chapter.

Discrimination of Diazo Compounds Toward Carbenoids: Copper(I)‐Catalyzed Synthesis of Substituted Cyclobutenes

In the last few years the role of diazo compounds in organic synthesis, particularly in cyclization reactions via metal carbenoids (metal: ruthenium, copper, rhodium, etc.) has been prominent. By taking advantage of the ease with which these metal carbenes collapse into the corresponding symmetrical alkenes (homocoupling), we and others have been able to access nonsymmetrical alkenes by the selective heterocoupling of diazoacetate esters with copper(I) and ruthenium(II) carbene complexes [Eq. (1)]. Interestingly, the metal-catalyzed selective cross-coupling reaction between two different diazo substrates has been reported recently [Eq. (2)].

Reactivity of Stabilized Vinyl Diazo Derivatives toward Unsaturated Hydrocarbons: Regioselective Gold‐Catalyzed Carbon–Carbon Bond Formation

The transition-metal-catalyzed decomposition of simple and unsaturated a-diazo carbonyl derivatives and the subsequent transfer of the carbene unit to saturated and unsaturated substrates is one of the most popular and powerful tools in organic synthesis. In particular, the [2+1] cycloaddition of alkenes and alkynes is recognized as a straightforward and useful approach for the construction of three membered carbocycles. Extensive studies have led to the achievement of high levels of chemo-, diastereo-, and enantioselectivity by employing mostly complexes of copper and rhodium. In spite of the potential of gold catalysis in C C bond formation, the first example of gold-catalyzed carbene transfer from ethyl diazoacetate to unsaturated substrates was reported in 2005 by Nolan, D az-Requejo, P rez et al. After this seminal contribution, few gold-catalyzed transformations involving simple diazo substrates have been reported. On the other hand, the synthetic potential of vinyl diazo derivatives has been well established, particularly in the cycloaddition area, and the reactivity of the carbene carbon versus the vinylogous carbon found to be dependent, at least in part, on the metal catalyst. Continuing with our interest in the development of new transition-metal-catalyzed transformations of stabilized vinyl diazo derivatives, as well as in gold catalysis, we herein report the first studies of the gold-catalyzed reaction of alkenyldiazo compounds and neutral alkenes that results in the room temperature selective C C coupling between the Csp2ACHTUNGTRENNUNG(alkene) and the Cg(alkenyldiazo) atoms. From a synthetic point of view, the alkenyl diazo compound behaves as a ethoxycarbonyl allyl cation in this process, allowing the regioselective preparation of g-substituted, a,b-unsaturated carbonyl compounds (Figure 1). This reactivity pattern contrasts with that observed when other common sources of alkenylgold carbenoids, such as propargylic esters or cyclopropenes, are used (2 + 1 cycloaddition). Preliminary studies on the extension of this new gold-catalyzed carbon– carbon bond-forming process to alkynes and arenes are also reported. For our exploratory studies, we investigated ethyl 2-diazobut-3-enoate (1 a) and 1-hexene (2 a, 4 equiv) as substrates and a series of gold catalysts (5 mol %) in dichloromethane at room temperature. To our delight, we found that the use of IPrAuNTf2 gave (2E)-ethyl deca-2,6-dienoate 3 a in moderate yield (67 %) as a nonseparable 1:1 mixture of 2E,6E/ 2E,6Z diastereoisomers (Scheme 1). This unprecedented

First [4+2] cycloaddition of alkynyl Fischer carbene complexes with heterodienes. Facile synthesis of 1,4-dihydropyridines from 1-azadienes

Neutral 1-azadienes react in a [4 + 2] fashion with alkynyl Fischer carbene complexes to afford regioselectively substituted 1,4-dihydropyridines.

Gold‐Catalyzed Functionalization of Unactivated C(sp3)H Bonds by Hydride Transfer Facilitated by Alkynylspirocyclopropanes

Transition-metal-catalyzed coupling reactions involving unactivated C(sp) H bonds constitute one of the most active research areas in both industry and academia. 2] In particular, the development of methods that enable C C bond formations through the selective cleavage of ubiquitous C(sp) H bonds is highly desirable as it allows for new retrosynthetic disconnections, thus minimizing the number of steps and the generation of waste. A major drawback of this transformation lies in the control of the selectivity. In general, selective functionalizations are achieved by the assistance of directing groups that bring the catalyst closer to the desired C H bond. Alternatively, good control of the selectivity has been reported by the intramolecular thermal or Lewis acid catalyzed 1,5-hydride transfer reaction (HT). In contrast to hydride transfer to electron-poor alkenes, the use of electronically unbiased alkynes as acceptor partners requires the assistance of platinum or gold catalysts. Thus, a variety of goldor platinum-catalyzed cleavages of C(sp) H bonds through intramolecular HT to alkynes have been described recently by the groups of Sames, Gagosz, and others. As a carbocation is initially generated, this strategy has been limited to C(sp) H bonds bearing a stabilizing functionality at the a position (OR, NR2, aryl; Scheme 1a). Considering this limitation, hydride transfer to alkynes from aliphatic, nonbenzylic, positions constitutes a challenging transformation. As part of our research into the synthesis and reactivity of alkynylcyclopropane derivatives, 10] we have recently reported the synthesis of spiro[2,4]heptane derivatives 1 whose particular structure makes them amenable for use in investigations of new metal-catalyzed processes. These compounds have severe geometrical restrictions that place an inactive methylene group close to the alkyne moiety. We hypothesized that this restricted geometry might facilitate the 1,5-hydride transfer to a metal-activated alkyne (Scheme 1b). Herein, we disclose a new gold-catalyzed hydride transfer from an unactivated C(sp) H bond to an alkyne, and the subsequent selective cyclizations. Initially, we studied the reactivity of spirane 1a in the presence of various gold catalysts. We were pleased to find that a high conversion of 1a was achieved when using cationic gold complex [(IPr)Au(NTf2)] in 1,2-dichloroethane (70 8C, 24 h; Scheme 2), thus yielding a mixture of compounds 2–4a (80 % conv., 2a/3a/4a = 2.5:1:1).

Gold‐Catalyzed Rearrangements: Reaction Pathways Using 1‐Alkenyl‐2‐alkynylcyclopropane Substrates

) allowed to design useful trans-formations based on the cleavage of the cyclopropane ring.Inthisscenario,itseemedtousthatthecatalytictransformationsof substrates containing the alkene–cyclopropane–alkyneconnectivity might be a promising approach. Surprisingly,transformations based on the 1-alkenyl-2-alkynylcyclopro-pane framework (1,5-enyne arrangement) are very rare.

Sequential Five-Component Construction of the Cyclopenta(e)- (1,3)oxazine Skeleton using Stable 2-Azetine Derivatives**

Small-ring heterocycles are of prominent importance because of their potential as bioactive compounds and synthetic building blocks. Whilst the chemistry of three-membered nitrogen heterocycles has been widely reported, studies on their four-membered counterparts have focused primarily on 2-azetidinones and, to a much lesser extent, azetidine rings. The 2-azetine system 1,2-dihydroazete, which has a strained cyclic enamine ring, is particularly elusive. Most 2-azetine compounds undergo spontaneous electrocyclic ring opening to afford their 1-azadiene analogues; as such, there are few examples of stable 2-azetines in the literature and those reported require electron-withdrawing substituents, for example, carbonyl, carboxyl, sulfonyl, or nitro groups, attached to the nitrogen atom. As a consequence, the chemistry of 2azetines remains largely unexplored, and has been predominantly focused on their potential as a precursor to azadienes. Moreover, there are no general synthetic routes to 2azetines. Although, the [2+2] cycloaddition of alkynes and imines appears to be a convenient route to this type of heterocyclic framework, only a few specific examples have been reported; in these cases, electron-rich alkynes, as ynamines, alkynyl selenides, or alkynyl sulphides, are able to form the expected 2-azetine skeleton, which is not isolated but rapidly opens to the azadiene system. The [2+2] cycloaddition of electron-poor alkynes and imines has only previously been suggested as an intermediate in the cyclization reaction between an alkynyl(ethoxy)carbene of tungsten and imine fluorenones to afford pyrroline derivatives. As part of our interest in Fischer-type metal carbenes, we have recently considered more-electrophilic metal carbenes, the so-called non-heteroatom-stabilized carbenes. These compounds are particularly useful in organic synthesis, and our preliminary results have revealed significant differences in the reactivity of both heteroatomand non-heteroatomstabilized systems. Herein, we report the [2+2] cycloaddition reaction of alkynyl-substituted (pentacarbonyl)chromium or -tungsten carbene complexes with imines as a suitable procedure for accessing stable 2-azetine derivatives. Moreover, the conjugation of the resulting azetine unit with the metal carbene allows for a facile synthesis of novel cyclopenta[e][1,3]oxazines involving treatment with alkynes. This threecomponent process (azetine, alkyne, and CO ligand) features cleavage of the azetine C3 C4 bond, rather than the expected N C4 bond, and the formation of three C C bonds and one C O bond (Scheme 1).

Single and Consecutive Cyclization Reactions of Alkynyl Carbene Complexes and 8-Azaheptafulvenes: Direct Access to Polycyclic Pyrrole and Indole Derivatives

The reactivity of alkynyl and enynyl Fischer carbene complexes towards 8-azaheptafulvenes is examined. Alkynyl carbenes 1 a-f undergo regioselective [8+2] heterocyclization with 8-aryl-8-azaheptafulvenes 2 a, b providing cycloheptapyrroles 3 and 4 with metal carbene or ester functionality at C3. Moreover, consecutive cyclization reactions are involved when enynyl carbenes are used. Thus, the cyclopenta[b]pyrrole framework 7 is formed by the consecutive [8+2] cyclization and cyclopentannulation reactions. The initially formed cyclopentannulation adduct can be intercepted through a Diels-Alder reaction with classic dienophiles to afford increasing structural complexity (compounds 8 and 9). More importantly, the construction of the indole skeleton is accomplished with a high degree of substitution and functionalization (compounds 11-15) by a one-pot sequence that involves [8+2] cyclization, R--NC or CO insertion, and ring closure.

Copper(I)‐Catalyzed [3+1] Cycloaddition of Alkenyldiazoacetates and Iminoiodinanes: Easy Access to Substituted 2‐Azetines

The copper(I)-catalyzed reaction of alkenyldiazoacetates and iminoiodinanes affords functionalized azetine derivatives. This process is consistent with the formation of an aziridinyldiazoacetate intermediate, which gives rise to the four-membered heterocycles by metal-catalyzed ring expansion. The resulting azetine structure is a direct precursor of azeditine-2-carboxylic acid derivatives (EWG = electron-withdrawing group).