Two-alkyne annulation

The benzannulation reaction with small alkynes such as 1-pentyne may generate a two-alkyne annulation product. In this case the original [3+2+l]-benz-annulation is changed to a [2+2+1+1]-benzannulation. After CO dissociation and insertion of the first alkyne, the coordinated a,/J-unsaturated moiety in the vinylcarbene complex is supposed to be replaced by the second alkyne. The subsequent reaction steps give the phenol 112 (Scheme 50). 

The selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

Steroid-type molecules, e.g., 48, were generated from (l-alkynyl)carbene complex 11 by [4+2] cycloaddition of a TBSO butadiene to the C2-C3 triple bond of lk and subsequent two-alkyne annulation to the M = C bond (Scheme 17).75 Other polycyclic compounds have been obtained similarly by insertion of several alkyne units tethered by a carbon chain.76,77 It should be noted that an annulation of an aromatic ring instead of a 1,4-cycIohexa-diene is achieved if the diene component contains a potential leaving group, as shown in Schemes 16 and 17. 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

A less efficient mode of the two-alkyne annulation is the intra-intermolecular reaction of an alkyne-containing carbene complex of the type (312) with a second alkyne. Under optimal conditions, these reactions will lead to moderate yields of bicyclic phenols of the type (313), which result from the assembly of pieces indicated by (315). The precursor dienones (314) can be isolated as minor products from these reactions.Applications of the two-alkyne annulations in organic synthesis have not yet been reported. 

Alkoxy iron complexes of the type (316) will also react with alkynes to give six-membered ring products that, like the two-alkyne annulation, are formally the result of a [2 -i- 2 -i- 1 + 1] cycloaddition. The formation of these pyrone complexes (317) have only been reported from the reactions of alkynes with iron-carbene complexes. These pyrones are also the only product from the reaction of an alkyne with any carbene complex which incorporates one alkyne, two carbon monoxides and the carbene ligand. 

In the presence of an excess of small alkynes the typical [3+2+1 jbenzannulation has to compete with a [2+2+1+lj (two-alkyne) annulation resulting from two consecutive alkyne insertion steps. The selectivity for this variant is increased for an intramolecular reaction. Diynyl-arylcarbene complexes 31 and 32, in which the carbene moiety is tethered by an appropriate spacer to two alkyne functionalities, are formed in a chemoselective Diels-Alder reaction of the more electron-deficient bond in the triyne carbene precursor complexes 35 and 36 with Danishefsky s diene a final thermal two-alkyne annulation affords the steroid skeleton 33. The sequence can be performed as a one-pot procedure in yields of 30%... 

Scheme 11.12 [2+2+1+1] (Two-alkyne) annulation towards the steroid skeleton.

One drawback to this alkyne annulation chemistry is that it requires either symmetrical alkynes or unsymmetrical alkynes in which the two substitutents on the internal alkyne are sterically quite different or else one obtains mixtures of regioisomers. One way to overcome this problem is to prepare the corresponding arylalkyne through catalytic Pd/Cu chemistry and then effect electrophilic cyclization using organic halides and a Pd catalyst (Scheme 8).9... 

Related cyclocotrimerizations of two alkyne molecules with isocyanates have also been achieved using cobalt and nickel catalysts [9], With respect to intramolecular versions, two examples of the cobalt(I)-catalyzed cycloaddition of a,co-diynes with isocyanates have been reported to afford bicyclic pyridones only in low yields, although 2,3-dihydro-5(lH)-indolizinones were successfully obtained from isocyana-toalkynes and several silylalkynes with the same cobalt catalysis [50], On the other hand, the cycloaddition of 1,6-diynes 20 with 4 equiv. of isocyanates proceeded in refluxing DCE under the ruthenium catalysis to afford bicyclic pyridones 58 in 58-93% yield (Scheme 4.21) [51], Both aryl and aliphatic isocyanates can be widely employed in this pyridone annulation. 

Dibenzoylacetylene and DM AD (review [2816] are useful reagents for cyclizing aminoheterocycles in this example, the amino and ring-nitrogen atoms in different rings are annulated by heating with either of the two alkynes [3768]. 

An efficient synthesis of functionalized carbazoles was developed by the palladium-catalyzed annulation of a variety of internal alkynes. This reaction involves arylpalladation of the alkyne, followed by intramolecular Heck olefination, and double bond isomerization. The iodoindole 588 reacts with the alkyne 589 in the presence of a catalytic amount of palladium(O) to give substituted carbazoles 590. In this reaction two new C-C bonds are formed in a single step. Higher reaction temperatures were necessary due to the low reactivity of the iodoindole (566) (Scheme 5.29). 

A wide range of substituted isoquinolines (93) have been synthesized via a highly efficient nickel-catalysed annulation of the r-butylimines of 2-iodobenzaldehydes (91) and various alkynes (92) examination of the regiochemistry of the reaction revealed the operation of two different alkyne insertion pathways.119... 

Attempted annulation of 3-iodoflavones, for example 428, by internal alkynes catalyzed by Pd(OAc)2 in the presence of NaOAc and LiCl yielded a mixture of two compounds (Scheme 73) <1998JOC2002>. While the expected benzoxanthenes (e.g., 429) were isolated as the minor compound, tetrasubstituted furans (e.g., 430) resulting from the electrophilic attack on the carbonyl oxygen atom by the vinylpalladium intermediate followed by pyrone ring opening were the major product. 

Another useful route involving formation of two bonds is based on palladium-catalyzed annulation of 2-iodoanilines with alkynes. As the use of trimethylsilyl acetylenes leads to regioselective formation of indoles bearing a TMS group at C-2 <1998JOC7652>, this approach has proven to be useful in the synthesis of optically active tryptophans <1999TL657>. In a typical example, the substituted o-iodoaniline 364 and the acetylene 365 were efficiently converted to the indole 366 (Equation 102), which could thereafter be transformed into 5,6-dimethyl-L-tryptophan <2001JOC4525>. 

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