Intramolecular kinetic control

A deviant reaction was observed when the AT-Boc-aziridinecarboxamide 44b was treated with LDA in THF as the base. Under these kinetically controlled conditions an intramolecular reaction of the amide nitrogen with the Boc group takes place leading to the bicyclic product 46 in which the aziridine ring is retained (Scheme 36) [45]. 

In summary, then, the orientation of electrophilic thallation can be controlled by an appropriate manipulation of reaction conditions. Under conditions of kinetic control, ortho substitution results when chelation of the electrophilic reagent (TTFA in the studies described above) with the directing substituent permits intramolecular delivery of the electrophile, and para substitution results when such capabilities are absent this latter result is an expression of the very large steric requirements of the bulky thallium electrophile. Under conditions of thermodynamic control, however, meta substitution is observed. 

Intramolecular nitroaldol reactions are a useful choice for the conversion of sugars into polyhydroxylated nitro cyclopentanes, nitro cyclohexanes and their derivatives.46 Baer et al. in the course of their studies on the cyclization of 6-deoxy-6-nitrohexoses under kinetic and thermodynamic control,47 established the reaction pathway involved in the formation of nitroinositols mediated by intramolecular Henry reactions. Firstly, a nitronate is formed and then, under thermodynamic control conditions, an epimerization occurs before cyclization. But, under kinetic controlled conditions, the cyclization occurs first.48... 

The preparation of 620, a tricyclic intermediate suited for elaboration into quadrone, has been reported by Monti and Dean Following introduction of the proper C5, stereochemistry by alkylation of 618 under kinetically controlled conditions, diketone 619 was subjected to acid-catalyzed rearrangement. After functional group manipulation, a tandem intramolecular aldol-pinacol rearrangement gave 620. 

The mechanism can be described by using a R —> M = M — Ox scheme. The fully reduced complex R is oxidized by a one-electron process to the thermodynamically unstable electronic isomer, M, which is formed by attack on the Ru11 center, in a kinetically controlled reaction. Then, M7 rapidly isomerizes via intramolecular electron transfer to M, the thermodynamically stable isomer. As the latter species has again a very reactive Ru11 site, the complete oxidation to Ox is consumed. A similar mechanism has been described for the related oxidations of the [(edta)RuIIpzRuII(NH3)5] complex (129). 

Intramolecular Sakurai reaction. Allylic and propargylic silanes can undergo a Lewis acid catalyzed intramolecular Sakurai reaction.1 In cyclization to hydrin-danones, the stereochemical outcome can differ from that obtained by fluoride ion catalysis (presumably kinetically controlled cyclization), equation (I).2... 

While the regiochemistry of simple electrophilic additions to double bonds is controlled by a combination of electronic (Maikovnikov rule), stereoelectronic (trans diaxial addition to cyclohexenes) and steric factors,9 the intramolecular nature of electrophilic heteroatom cyclizations introduces additional conformational, stereoelectronic and entropic factors. The combination of these factors in cyclofunctionalization reactions results in a general preference for exo cyclization over endo cyclization (Scheme 4).310 However, endo closure may predominate in cases where electronic or ring strain factors strongly favor that mode of cyclization. The observed regiochemistry may differ under conditions of kinetic control from that observed under conditions of thermodynamic control. 

Intramolecular amidomercuration of carbamate derivatives to generate 2,6-disubstituted piperidine systems (equation 113 and Table 31) proceeds with low selectivity under conditions of kinetic control (cis.trans = 40 60),246 248 but cyclization under conditions of thermodynamic control highly favors the cis isomer (cis. trans > 98 2).246 Interestingly, only the cis isomer was isolated from cyclization with phe-nylselenenyl chloride in the presence of silica gel.216 ... 

The extent of kinetically controlled formation of the carboxonium ions 31 depends on the nature of R1 and Yy. The possible existence of 31 allows formation of acylated enols 32 (Y = R3CO), which are analogous with w-acylaminostyrene derivatives. As is known, the latter compounds easily undergo an intramolecular acid-catalyzed cyclization to isoquinolines (the Pictet-Gams reaction) (80T1279). 

Stabilized hthiated sulfoximines (112) undergo highly diastereoselective Michael additions to cyclic enones at —78 °C under kinetically controlled conditions. At room temperature, the initially formed adducts (113) undergo intramolecular substitution of the sulfonimidoyl group, with inversion of configuration to afford the corresponding cyclopropanes (114).92... 

In the course of the total synthesis of enmein, Fujita and co-workers (7) have discovered that the intramolecular cyclization of the enolate 23 of the corresponding tetracyclic keto-aldehyde at room temperature gave only ketol 24. However, when the same reaction is conducted at 60°C, thermodynamically controlled conditions prevail, and the epimeric product 25 is obtained. Inspection of molecular models indicates that the kinetically controlled product 24 is again the result of an anti peri planar arrangement of the enolate and the aldehyde double-bonds. Also, as in the previous examples, the isomer 25 comes from a synclinal arrangement of the reacting functional groups. 

Formation of a highly electrophilic iodonium species, transiently formed by treatment of an alkene with iodine, followed by intramolecular quenching with a nucleophile leads to iodocyclization. The use of iodine to form lactones has been elegantly developed. Bartlett and co-workers216 reported on what they described as thermodynamic versus kinetic control in the formation of lactones. Treatment of the alkenoic acid 158 (Scheme 46) with iodine in the presence of base afforded a preponderance of the kinetic product 159, whereas the same reaction in the absence of base afforded the thermodynamic product 160. This approach was used in the synthesis of serricorin. The idea of kinetic versus thermodynamic control of the reaction was first discussed in a paper by Bartlett and Myerson217 from 1978. It was reasoned that in the absence of base, thermodynamic control could be achieved in that a proton was available to allow equilibration to the most stable ester. In the absence of such a proton, for example by addition of base, this equilibration is not possible, and the kinetic product is favored. 

The relative power of DMG (Table 1), established by experiments at low temperature and short reaction times and thus crudely representative of kinetic control conditions, may vary with inter- and intramolecular competition, conditions, and sometimes results are conflicting. Nevertheless, for synthetic practice this hierarchy follows a qualitative order consistent with CIPE and serves as a useful predictive chart. For thermodynamic control conditions, the pchart of Fraser of 12 DMG [27], determined by equilibrium deprotonation using LiTMP (pka=37.8), is a guide for lithium dialkylamide DoM reactions. 

Exploring different methods for the intramolecular radical cyclization of 78 (Scheme 15)95, Usui and Paquette observed that (TMS SiH under normal conditions affords the expected functionalized diquinane 79 in 80% yield and in a a fi ratio of 82 18. MM2 calculations suggest it is the result of a kinetic controlled process. It is worth mentioning that the endothermic reaction 42 is expected to be one of the propagation steps in this chain process (vide infra). By replacing the silane with tin hydride under similar experimental conditions, the unexpected product 80 was obtained in a 77% yield. 

The kinetically controlled N-protonation product (173) of 2-methyl- l-(/7-methyl-styryl)piperidine (172) was isolated280,281 as colourless crystals by passing dry HC1 into a solution of 172 in benzene below 0 °C. When the resulting enammonium salt 173 was warmed in methanol, it changed to the more stable iminium salt 174 (equation 11). Experimentally it was shown that this isomerization is not an intramolecular process33, which as a concerted [1,3] shift would not be symmetry-allowed according to the Woodward-Hoffmann rules282. 

The propensity for intramolecular transannular bonding could be controlled during lithium aluminum hydride reduction, the symmetric lactol 560 being obtained from 543 in good yield, 431 The indicated structure was not the product of kinetic control rather, equilibration of the hydroxyl groups was noted to occur during workup and recrystallization. When dissolved in thionyl chloride, 560 was quantitatively converted to bis-chloro ether 561 (Scheme 82). On treatment with... 

Intramolecular amidomercuration,6 Kinetically controlled amidomercuration [Hg(OAc)2, THF] of the 8-alkenylcarbamate 1 followed by reduction results in highly stereoselective cyclization to /rans-2,5-dimethylpyrrolidines (equation I). Amidomercur-... 

In order to predict the stereochemical outcome of a cyclization, some rules have been proposed based on a model for the attack of an electrophile, under kinetic control, to an alkene containing an internal nucleophile. The selectivity is determined by the relative affinity of the diastereotopic face of the double bond towards a proton syn to H in an OH-in-plane-conformer, or syn to OH in a H-in-plane-conformer, and the cyclization involves a probable intramolecular attack on a 7i-compIex. In fact, when a hydroxy or an alkoxy group is present, the electrophile preferentially attacks the OH-in-plane-conformer from the face of the double bond syn to the allylic hydrogen 22. Thus, starting from terminal double bonds, the ci.v-diastereomer is prevalent in the reaction mixture. 

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