Cyclization 6- endo-dig

IH of 2-alkynylanihnes has been also studied in the presence of molybdenum [284], palladium [276, 277, 281], and gold catalysts [276]. It provides indoles in low to good yields as a result of 5-Endo-Dig cyclizations (Eq. 4.73) [277]. 

Knochel demonstrated the effectiveness of soluble potassium or cesium alkoxides such as KO Bu or CsO Bu as well as KH in iV-methylpyrrolidinone (NMP) for promoting the 5-endo-dig cyclizations of 2-alkynylanilines to 2-substituted indoles in solution or the solid-phase <00AG(E)2488>. Alternatively, Cacchi coupled a palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides with the addition of benzyl bromide or ethyl iodoacetate to afford 2-substituted-3-benzyl or 3-indolylcarboxylate esters, respectively <00SL394>. Yamamoto reported a new palladium catalyzed indole synthesis in which 2-(l-alkynyl)-Ar-alkylideneanilines 117 give 2-substituted-3-(l-alkenyl)indoles 118 directly from the imine by the in situ coupling of an aldehyde with the alkynylaniline <00JA5662>. 

In the presence of a pendant hydroxyl group, the Sonogashira alkynylpyridine adduct can cyclize in situ to produce 2-substituted furopyridines [119-121], Thus, alkynylpyridinol 148, from the coupling of 2-iodopyridin-3-ol and phenylacetylene, underwent a spontaneous 5-endo-dig cyclization promoted by either Pd or Cu to give 2-phenylfuropyridine 149 [118]. 

When subjected to mercury acetate the ynone 78 underwent a 5-endo-dig cyclization and after work-up with aqueous sodium chloride, furnished the pyrrolinones 79 and 80 in a ratio of 89/11. The mixture of pyrrolinones was reduced directly with sodium borohydride to the iST-Boc-pyrrolidinol 81 which was obtained as a single diastereoisomer. Reduction of the carbamate with lithium aluminum hydride gave (+)-preussin (2) in 37% overall yield. 

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]. 

It might, at first glance, come as a surprise that, despite the ban on 5-endo-trig cyclizations, 5-endo-dig cyclizations are allowed. A possible reason for this observation is that intramolecular nucleophilic or electrophilic attack at an alkyne can proceed with the substrate in a flat conformation, because two orthogonal jt (or jt) orbitals are available. Similarly, hydroxymethyl allenes cyclize on treatment with a base (Scheme 9.7), because the terminal Jt orbital of the allene and the hydroxymethyl group can readily achieve a synperiplanar orientation. Intramolecular... 

Scheme9.7. Examples of 5-endo-dig cyclizations [1 7-21] and 5-endo-trig cyclizations of allenes [22],...

A stereochemical study of the synthesis of unsaturated 1,4-aminoalcohols via the reaction of unsaturated 1,4-alkoxyalcohols with chorosulfonyl isocyanate revealed a competition between an retentive mechanism and an SnI racemization mechanism, with the latter having a greater proportion with systems where the carbocation intermediate is more stable.254 An interrupted Nazarov reaction was observed, in which a nonconjugated alkene held near the dienone nucleus undergoes intramolecular trapping of the Nazarov cyclopentenyl cation intermediate.255 Cholesterol couples to 6-chloropurine under the conditions of the Mitsunobu reaction the stereochemistry and structural diversity of the products indicate that a homoallylic carbocation derived from cholesterol is the key intermediate.256 l-Siloxy-l,5-diynes undergo a Brpnsted acid-promoted 5-endo-dig cyclization with a ketenium ion and a vinyl cation proposed as intermediates.257... 

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>. 

Agrofoglio et al. reported52 the synthesis of furo[2,3-J]pyrimidines 25 via AgN03-catalyzed 5-endo-dig cyclization (Scheme 5.12). Furo[2,3-< /1pyrimidines 25 were obtained through activation of the alkynyl moiety of 24 by AgN03 (0.2 equiv), giving intermediate L, followed by the 5-endo-dig cyclization. 

A gold(I)-catalyzed domino reaction sequence involving pentenynyl tosylamides led to the formation of 2,3-disubstituted pyrroles containing a quaternary center in the 2-substituent <07OL3181>. The mechanism of the reaction involved a 5-endo-dig cyclization followed by an aza-Claisen rearrangement. 

Dihydroisoxazoles were prepared by 5-endo-dig cyclization of O-propargylic... 

Employing a 5-endo-dig cyclization process catalyzed by />-toluenesulfonic- or sulfinic acid, the amino esters 8 were smoothly converted to the pyrroles 9 in refluxing toluene. Both acid catalysts gave comparable results in terms of yield <03SL2258>. 

The total synthesis of pyrrolidinol alkaloid, (+)-preussin was achieved in five efficient transformations from commercially available fert-Boc-(S)-phenylalanine in the laboratory of S.M. Hecht. The key step involved the Hg "-mediated 5-endo-dig cyclization of ynone substrate affording the desired pyrrolidinone which, in two more steps, was converted into the natural product. 

Heterocyclization. Formation of A-tosyl-2-iodomethylaziridine from A-tosyl-allylamine requires iodine and NaH, whereas Ij-LiAl(OBu ) mediates cyclization of allyl A-acylcarbamates." A route to 4-iodo-2,3-dihydropyrroles by iodine-induced cyclization of homopropargylic sulfonamides involves a 5-endo-dig cyclization. ... 

HeterocycUziotion a -Aminoalkynones undergo a 5-endo-dig cyclization that results in pyrrolinones. This process has been applied to a synthesis of (+)-preussin. 

The rare-earth metal-catalyzed cyclization of aminoalkenes, aminoalkynes and aminodienes generally produces exclusively the exocyclic hydroamination products. The only exception was found in the cyclization of homopropargylamines leading to the formation of the endocyclic enamine product via a 5-endo-dig hydroamination/cyclization (32) [142], most likely due to steric strain in a potential four-membered ring exocyclic hydroamination product. Interestingly, the 5-endo-dig cyclization is still preferred even in the presence of an alkene group that would lead to a 6-exo hydroamination product [142]. 

A titanium-catalyzed hydroamination of 1,4-diynes and 1,5-diynes produces 1,2,5-trisubstituted pyrrroles in one synthetic step <04OL2957>. Treatment of 1,4-diyne 33 with titanium complex 34 led to the formation of pyrrole 35 via a hydroamination to an imino alkyne followed by an intramolecular 5-endo dig cyclization. Another transition metal-mediated pyrrole... 

A final example serves to both highlight the potential for further developments of 5-endo-dig cyclizations and to encourage a search for novel electrophilic triggers reaction of the alkynyl hydroxylamines 273 with zinc iodide and DMAP in dichloromethane delivers excellent yields of the isoxazolines 274 . It therefore seems very likely that 5-endo cyclizations in general, those already developed and new versions to come, will make many useful contributions to synthetic organic methodology. 

The last step looks a long stretch, but you saw in Chapter 31 that 5-endo-dig cyclizations are favourable (p. 813). 

Figure 8.25 Cooperative through bond and through space interactions responsible for a-aromaticity in the 5-endo-dig cyclization transition state.

Even though stereoelectronic effects are usually associated with increased reactivity, this is only true when such effects are displayed in the TS. When considered more broadly, stabihzing effects can also be unproductive when they operate in starting materials but not the transition states. For example, the barrier of the elusive radical 5-endo-dig cyclization in Figure 10.7a, exceeds 20kcal/mol because benzyUc stabilization of the reactant is lost upon the 90° rotation of the radical orbital needed to reach the cyclization TS. On the other hand, 5-endo-dig cyclization in a constrained polycyclic system in Figure lO.Tb does not suffer from reactant stabihzation and shows 9kcal/mol lower activation barrier. ... 

Figure 10.7 (a) Loss of a stabilizing stereoelectronic effect (i.e. benzylic stabilization of the vinyl radical) imposes additional penalty on the 5-endo-dig cyclization. (b) The penalty can be removed via conformational constraints in the reactant. 

Alabugin, I. V., Manoharan, M. (2005). 5-Endo-dig Cyclizations - the Poor Cousins of the Radical CycUzation Family. Journal of the American Chemical Society, 127, 9534—9545. 

Control of reactive conformations We have outlined the electronic origins and conformational consequences of the gauche effect in Chapter 6 and already illustrated its utility for the design of NMR probes of chirality (Chapter 10). However, the list of applications of the gauche effect in the control of chemical structure and reactivity is much more diverse. For example, the gauche effect has been ntilized to achieve efficient and strain-free conformational control in the first example of the elusive 5-endo-dig cyclization of... 

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