Cyclizations 6- endo-dig

A unique method to generate the pyridine ring employed a transition metal-mediated 6-endo-dig cyclization of A-propargylamine derivative 120. The reaction proceeds in 5-12 h with yields of 22-74%. Gold (HI) salts are required to catalyze the reaction, but copper salts are sufficient with reactive ketones. A proposed reaction mechanism involves activation of the alkyne by transition metal complexation. This lowers the activation energy for the enamine addition to the alkyne that generates 121. The transition metal also behaves as a Lewis acid and facilitates formation of 120 from 118 and 119. Subsequent aromatization of 121 affords pyridine 122. 

Fig. 22 Radicals used to study the effect of strain on the efficiency of 5-exo and 6-endo-dig cyclizations.

Stabilized ketene 6S. For l, 2 -disubstituted epoxide, species 6S undergoes 6-endo-dig electrocyclization (path b) [24] to form the six-membered ketone 66, ultimately giving naphthol products. l, 2, 2 -Trisubstituted epoxide species 6S undergoes 5-endo-dig cyclization (path a) to give the ketone species 67, finally producing l-alkylidene-2-indanones. The dialkyl substituent of the epoxide enhances the 5-endo-dig cyclization of species 65 via formation of a stable tertiary carbocation 67. We observed similar behavior for the cyclization of (o-styryl)ethynylbenzenes [15, 16]. Formation of 2,4-cyclohexadien-l-one is explicable according to 6-endo-dig cyclization of a ruthenium-stabilized ketene, vhich ultimately afforded the observed products [25]. 

Another rhodium vinylidene-mediated reaction for the preparation of substituted naphthalenes was discovered by Dankwardt in the course of studies on 6-endo-dig cyclizations ofenynes [6]. The majority ofhis substrates (not shown), including those bearing internal alkynes, reacted via a typical cationic cycloisomerization mechanism in the presence of alkynophilic metal complexes. In the case of silylalkynes, however, the use of [Rh(CO)2Cl]2 as a catalyst unexpectedly led to the formation of predominantly 4-silyl-l-silyloxy naphthalenes (12, Scheme 9.3). Clearly, a distinct mechanism is operative. The author s proposed catalytic cycle involves the formation of Rh(I) vinylidene intermediate 14 via 1,2-silyl-migration. A nucleophilic addition reaction is thought to occur between the enol-ether and the electrophilic vinylidene a-position of 14. Subsequent H-migration would be expected to provide the observed product. Formally a 67t-electrocyclization process, this type of reaction is promoted by W(0)-and Ru(II)-catalysts (Chapters 5 and 6). 

Whereas acid-catalysed cyclization of (21) undergoes the 6-endo-dig cyclization to afford (23), as discussed earlier, application of a base results in the formation of (22) as a product of 5-exo-dig ring closure.39... 

The palladium-catalyzed cyclization of ( )-3-alkynyl-3-trifluoromethyl allylic alcohols proceeds via a favourable 6-endo-dig cyclization due to the electron withdrawing properties of the trifluoromethyl group to afford 4-trifluoro-methyl-27/-pyrans (Equation 8) <2000TL7727>. 

Under palladium(n) catalysis 2-alkynylbenzyl alcohols 136 can cyclize by either a 5-exo-dig process to form (Z)-l-alkylidene-l,3-dihydrobenzofurans 138 or a 6-endo-digprocess to afford 177-isochromenes 137 (Equation 66). Lower solvent polarity and alkyl, rather than aryl substitution of the alkyne favour a 6-endo-dig cyclization (Table 3) <2003T6251>. 

Allylation of 2-alkynylbenzaldehydes followed by 6-endo-dig cyclization can be mediated by a palladium(ll)-copper(l) bimetallic system to afford l -allyl-l //-isochromcncs. In a similar fashion, cyanation and 6-endo-dig cyclization of 2-alkynylbenzaldehydes furnishes l -cyano-1 //-isochromcncs (Equation 68) <2005T11322>. 

A tungsten-catalyzed cycloisomerization of the D-ribose-derived alkynyl alcohol 181 provides a 6-endo-dig cyclization route to 3,4-dihydropyrans. Excellent endo-modc selectivity, and hence minimal tetrahydrofuran production is... 

A 6-endo-dig cyclization of the homopropargylic alcohol 182 is achieved by careful manipulation of the ruthenium catalyst and reaction conditions to afford the 3,4-dihydropyran 183 (Equation 83) <2002JA2528>. Likewise, alkynols 184 undergo rhodium(i) mediated 6-< 4o-selective cyclizations to afford 3,4-dihydropyrans in good yield (Equation 84) <2003JA7482>. 

Iridium(m) hydrides catalyze a 6-endo-dig cyclization of ortho-alkynyl benzoic acids to afford isocoumarins (Equation 323) <2005OL5437>. Likewise, the intramolecular cyclization of ortho-alkynyl benzoic acids can be catalyzed by palladium(ll) and silver(ll) to afford isocoumarins as the major product along with formation of the 5-endo-dig cyclization product (Equation 323) <1999S1145, 2000T2533>. 

This observation is not related to traces of base or acid from the silver salts used since control experiments mled out this possibility. It was known from the literature that the 5-exo-dig versus 6-endo-dig cyclization mode could depend on the nature of the carbonyl group,56 57 of the alkyne substituent,58 59 and of the nature60 61 and oxidation state62 of the metallic source used. Also, work from Yamamoto25 demonstrated the importance of both a- and Jt-Lewis acidity properties of silver(I) complexes. Therefore, depending on the silver salt used, two mechanistic pathways were proposed (pathways A and B, Scheme 5.15). 

With gold(III), no conversion was observed (Table 12.16, entry 1) the coordina-tively saturated gold complex gave a low yield of the 6-endo-dig cyclization product (entry 2). The cationic gold complex with a free coordination site gives an excellent yield with the same selectivity (entry 3) the same is true for AgSbF6 alone (entry 4). But this is not true for all silver catalysts with a systematic increase in the pK.A value of the conjugate acid of the silver counterion, increased portions of the 5-exo-dig product were produced (entries 5 and 6). 

Dihydropyran formation by a 6-endo-dig cyclization from 4-alkynols is achieved with (MeCN)2PdCl2 as catalyst, Pd(OAc)2 is much inferior for structurally complex substrates as that shown below. ... 

Alkylidene phthalides are produced from 5-exo-dig cyclization of o-alkynylbenzoic acids. However, concomitant generation of isocoumarins via 6-endo-dig cyclization is normally problematic [63]. 

The 3-substituted pentynoic acid 149 underwent 6-endo-dig cyclization to give rise to the y-arylidenebutyrolactone 150 using TFP as a ligand [50]. On the other... 

With ortAosubstituted imine moieties, activation of arylalkynes by complex 1 as well as In(OTf)3 and NiCl2 led to 6-endo-dig cyclization, forming isoquinolinium intermediates. These reactive intermediates were trapped with various nucleophiles including allylstannane, hydride from the Hantzsch salt, active methylene compounds, and alkenylboronic acids, yielding 1,2-dihydroiso-quinolines (eq 15). ... 

The gold-catalyzed rearrangement of vinyl propargyl ethers such as 49 was reported by Toste and Sherry. The intermediate oxonium 50 was initially formed via a 6-endo-dig cyclization with the propargylic substituent occuping a pseudoaxial orientation to avoid A -strain with the alkenyl gold moiety. Allenic aldehyde 51 was then formed as 50 collapsed via a fragmentation pathway. ... 

Excellent yields of isocoumarin-type compounds are obtained via 6-endo-dig cyclization of 2-(2-arylalkynyl)quinoline-3-carboxylates using KOH in MeOH at room temperature (Scheme 70) (13T1822). 

As shown in Scheme 43, treatment of o-ethynylbenzoic acids with PdCl2(MeCN)2 catalyst in THF results in the 6-endo-dig cyclization to give 3-substituted isocoumarins as the major product. ... 

Sivaraman M, Muralidharan D, Perumal PT (2012) Synthesis of novel 9-(l-iodovinyl)acri-din-(27/)-one through iodine mediated cascade 6-endo-dig cyclization followed by condensation and 3,3-sigmatropic migration of 2-aminophenyl propynyl oxyenone. Tetrahedron Lett 53 6039-6043... 

CuBr efficiently catalyses an alternative reaction pathway of 67, namely a 6-endo-dig cyclization to give pyridine derivatives. 

The author next envisioned the preparation of benzothiazine-1,1-dioxide derivatives 15 through domino MCR and cyclization. Since benzo[e][l,2]thiazine-1,1-dioxides are widely found in biologically active compounds including nonsteroidal anti-inflammatory drugs (NSAIDs) [15-22], various approaches to construct this structure have been reported [23-33]. The author expected that the use of such a sulfonamide as 14, an aldehyde, and a secondary amine in the presence of a copper catalyst would bring about a Mannich-type reaction followed by 6-endo-dig cyclization (related synthesis of thiazines has been already reported, see [34, 35]) to afford a benzo[e][l,2]thiazine 15. The reaction of A-methyl and N-ethylsulfonamides 14a and 14b under standard conditions gave the desired ben-zothiazines 15a and 15b, respectively, but in low yields (34 and 37%, respectively, entries 1 and 2, Table 8). Considering that acidity of the amide proton in 14a and... 

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