The Intramolecular Addition

An analogous scheme has been proposed to explain the formation of the inverted alcohol (in some cases in 100% yield) observed during photolysis of nitrate esters of carbohydrates.  

Another possibility is the observation of j9-scission of a cyclic ether 

Although the reverse process is certainly very favored, free radical intramolecular addition to the carbonyl bond has been reported in some instances. The selectivity toward the carbon or the oxygen atom is very high but the reasons for this are not clear and more exhaustive studies are required. 

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Amines undergo aminopalladation to alkynes. The intramolecular addition of amines to alkynes yields cyclic imines. The 3-alkynylamine 273 was cyclized to the 1-pyrroline 274, and the 5-alkynylamine 275 was converted into the 2,3,4,5-tetrahydropyridine 276[137]. Cyclization of o-(l-hexynyl)aniline (277)... 

The synthetic application of reactions based upon the intramolecular addition of a carbanion or its enamine equivalent to a carbonyl or nitrile group has been explored extensively. One class of such reactions, namely the Dieckman, has already been discussed in Section 3.03.2.2, since ring closure can often occur so as to form either the C(2)—C(3) or C(3)—C(4) bond of the heterocyclic ring. Some illustrative examples of the application of this type of ring closure are presented in Scheme 46. 

An unusual case of addition of a carbanion to an unconjugated carbon-carbon double bond is shown in Scheme 47a. The subsequent transfer of the amide group is also noteworthy (80CC1042). The intramolecular addition of a carbanion to an aryne is a more widely established process. Such reactions have been applied to the synthesis of indoles (Scheme 47b) (75CC745> and oxindoles (Scheme 47c) (63JOC1,80JA3646). 

The reaction of the carbinol 198 with acetone leads to dienic 1,3-dioxolanes 200 as a result of the intramolecular addition of the hydroxyl group of the intermediate hemiacetal 199 to its triple bond (73ZOR1594). 

This section describes Michael-analogous processes in which, mostly under electrophilic conditions, ally - or alkynylsilanes undergo addition to enones or dienones (Sakurai reactions). The intramolecular addition of allylsilanes is an extremely useful reaction especially for the construction of carbocyclic ring systems, which occurs in a diastereoselective manner, in many cases with complete asymmetric induction. 

For 10 years, attention has been focused on the intramolecular additions ofallylic and alkynyl-silanes to enones. In early studies, a variety of Lewis acids were tested and reaction conditions were optimized to make this reaction a powerful tool in the synthesis of spiro-annulated, and 1,2-fused ring systems, which can be utilized in the total synthesis of natural products34,35. 

Analogous to the allylsilane cyclizations, alkynylsilanes can also be used to synthesize 1,2-fused bicyclic compounds. The intramolecular addition of 4-[5-(trimethylsilyl)-3-pentynyl]-2-cyclo-hexenone proceeded smoothly in the presence of various Lewis acids, yielding functionalized cw-fused octahydro-5/f-inden-5-ones containing the synthetically useful terminal allene unit45. 

The intramolecular Michael addition of acyclic systems is often hampered by competing reactions, i.e., aldol condensations. With the proper choice of Michael donor and acceptor, the intramolecular addition provides a route to tram-substituted cyclopentanones, and cyclopentane and cyclohexane derivatives. Representative examples are the cyclizations of /3-oxo ester substituted enones and a,/J-unsaturated esters. 

Jones and Lewton250 have also demonstrated the utility of the intramolecular addition of sulfenic acids to olefins as a stereospecific method for the synthesis of thiolan 1-oxides. 

Normant and coworkers50a have recently studied the intramolecular addition of nucleophiles to vinyl sulfones. The presence of the sulfonyl group in equations 58 and 59 is essential for the disfavored 5-endo-trigonal closure5013. In contrast, the corresponding sulfoxide gives no cyclic product when treated with potassium hydride and only decomposition occurs. 

A somewhat unusual sequence to generate azepanones 80 involved the intramolecular addition of hydroxylamines to alkynes 76 to form cyclic nitrones 77. A vinyl magnesium bromide addition at low temperatures and a reduction with TiCls followed by N-Boc protection led to the azepane 78. Double bond bromination and subsequent RUO4 oxidation gave the lactam 79. Several further steps allowed the generation of the lactam structure 80 proposed for d,/-aca-cialactam, but the spectral data of the synthetic material differed from that of the natural product (Scheme 16)] [23 a, b]. 

The intramolecular addition of the O-H bond to alkynes catalyzed by palladium complexes has been developed by K. Utimoto et al. (Eq. 6.59) [104]. An alkynyl alcohol can be converted to a cyclic alkenyl ether in the presence of a catalytic amount of [PdCl2(PhCN)2 or [PdCl2(MeCN)2] in ether or THE at room temperature. When the reaction was carried out in MeCN-H20 under reflux in the presence of a catalytic amount of PdCl2, hydration of the acetylenic alcohol occurred and the ketoalcohol was obtained in good yield instead. 

A stannanimine has been prepared from a highly hindered diazastanny-lene and 2,6-diisopropylphenylazide.88 The stannanimine is stable in solution at -30°C, but rearranges within two weeks by the intramolecular addition of a C—H bond of one of the isopropyl groups across the Sn=N bond. 

One of the most interesting reactions of this type involves the intramolecular addition of the organolithium derivative to the aryne (13) which is derived from the dilithio-compound (12) 28>. This leads to the remarkably stable organolithium compound (14) which reacts with water to form the expected heptafluorobiphenylene, and with bromine to form 1-bromoheptafluorobiphenylene. 

Phenylthio)nitroalkenes are also excellent intermediates for the synthesis of other heterocyclic ring systems. For example, tetrahydropyran carboxylic acid derivatives are formed by the intramolecular addition of oxygen nucleophile to l-(phenylthio)nitroalkene predominantly as the m-isomer (9.1 1) (see Eq. 4.40). The reaction may proceed via the chair-like transition state with two pseudo-equatorial substituents.50... 

The intramolecular addition of alkynyl-substituted a-diazoketones is catalyzed by Rh2(OAc)4 to give transient cyclopropenes, which spontaneously rearrange to vinylogous a-keto carbene intermediates for further carbon-skeleton transformations [54]. 

The intramolecular addition of sulfur ylides to imines (e.g. 72) has proven to be an excellent route to fused-ring aziridines (e.g. 73) <06AG(I)7066>. The addition of a sulfonamide to a vinylsulfonium salt leads to the formation of the sulfur ylide 72. The ylide then undergoes an intramolecular addition to form the product fused-ring aziridine 73. This method has also been used for the synthesis of fused-ring epoxides. 

The intramolecular addition of an enone to an in situ generated ketene has been utilized in the synthesis of a tricyclodecanedione derivative (4.52) 464). 

On the basis of these results we embarked on a systematic study on the synthesis of vinyl cations by intramolecular addition of transient silylium ions to C=C-triple bonds using alkynyl substituted disila alkanes 6 as precursors.(35-37) In a hydride transfer reaction with trityl cation the alkynes 6 are transformed into the reactive silylium ions 7. Under essentially nonHnucleophilic reaction conditions, i.e. in the presence of only weakly coordinating anions and using aromatic hydrocarbons as solvents, the preferred reaction channel for cations 7 is the intramolecular addition of the positively charged silicon atom to the C=C triple bond which results in the formation of vinyl cations 8-10 (Scheme 1). 

In 1987, Parsons et al. reported the intramolecular addition of alcohols to 1,2-alle-nyl sulfoxides in the presence of NaH [96],... 

Especially with Hg(II) it was often possible to obtain directly the vinylmercury species as a stable compound, for example in the cydization of 66 to 67 [20] or the formation of 69 from 68 (Scheme 15.15) [31]. This is in complete accord with the intermediate 7 in the mechanistic model for the intramolecular addition of nucleophiles to the allene unit (Scheme 15.1). 

For example, the UMP2 level of theory performs poorly, the RB3LYP approach predicts higher (by ca. 5-6 kJ/mol) barriers than its UB3LYP counterpart, and the G3(MP2)-RAD level of theory gives a higher barrier than the CBS-RAD method. One noticeable difference is the absence of a significant basis-set effect in the DFT calculations on the intramolecular addition. 

Intramolecular photoaddition of tertiary amine and styrene moieties has been extensively studied by Aoyama29 and Lewis group28,30,31 (equations 4-8). Equations 4 and 5 show that if the intramolecular additions result in the formation of a five- or six-membered ring, the product yields are excellent. Highly regioselective intramolecular proton transfer is proposed to occur via least motion pathways from the lowest energy... 

The electrochemical oxidation of 4-(2 -alkenylphenyl)phenols (32) in MeCN/ MeOH affords spirodienones (33) arising from cyclization by the intramolecular addition of the 4-position of the phenol to the olefinic side chain and... 

The intramolecular addition of acylcarbene complexes to alkynes is a general method for the generation of electrophilic vinylcarbene complexes. These reactive intermediates can undergo inter- or intramolecular cyclopropanation reactions [1066 -1068], C-H bond insertions [1061,1068-1070], sulfonium and oxonium ylide formation [1071], carbonyl ylide formation [1067,1069,1071], carbene dimerization [1066], and other reactions characteristic of electrophilic carbene complexes. 

Similar to the intramolecular addition of neutral carbon-centered radicals to alkenes, the formation of radical cations starting from alkenes with subsequent cyclization offers a convenient method for constructing carbocyclic ring systems. In contrast to the regioselective 1,5-ring closure (5-cxo-trig cyclization) of the... 

The intramolecular addition of silyl radicals to aromatic rings has also attracted some attention. Early work on the silyl radical obtained by the reaction of silanes 41 with thermally generated t-BuO radicals at 135 °C showed the formation of rearranged products only for = 3 or 4, whereas for = 1, 2, 5, and 6 no rearrangement took place [20],... 

The above-described synthetic strategy has also been adapted to the cycliza-tion of acyl radicals [57]. Two examples are given in Reaction (7.47). The intramolecular addition of acyl radicals to the oxauracil moiety is also an efficient reaction for the construction of five-, six-, and seven-membered rings. By replacing the radical acceptor with oxathymine, an additional stereo-genic centre at C5 position is introduced. 

The radical adduct obtained by the addition of (TMS)3Si to the keto azide 66 underwent an opening of the cyclopropyl ring, with formation of 67 as intermediate, prior to the intramolecular addition to the azido group [60]. After tosylation the final product was obtained in 61 % yield. 

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