Reaction, intramolecular

Intramolecular reactions are faster and cleaner than intermolecular reactions. When we... 

The strategy of using intramolecular reactions to set up the correct relationslup between two groups is of more general importance. We obviously want to disconnect bonds a and b in TM 328 so that we add a four carbon fragment to PhOMe in the synthesis. 

It will be easy to put in bond a because it is para to the MeO group, but bond b might be difficult Tire strategy is to put in bond a first and use an intramolecular reaction to force bond b to go in the right place. Succinic anhydride is a convenient four carbon electrophile ... 

Intramolecular reactions of electron donor and acceptor sites in cyclic starting materials produce spirocyclic, fused, or bridged polycyclic compounds. 

In a similar reaction the bis-tosylate shown below was to be converted into a bis-malonate derivative. In this cyclic derivative both groups are hold closely together and intramolecular reactions proved to be so much faster than intermolecular substitution under all ex-... 

We begin with the discussion of intramolecular reactions. An example of a regioselec-tive Dieckmann condensation (J.P. Schaefer, 1967) used an educt with two ester groups, of which only one could form an enolate. Regioselectivity was dictated by the structure of the educt. 

Intramolecular reactions between donor and acceptor centres in fused ring systems provide a general route to bridged polycyclic systems. The cts-decalone mesylate given below contains two d -centres adjacent to the carbonyl function and one a -centre. Treatment of this compound with base leads to reversible enolate formation, and the C-3 carbanion substitutes the mesylate on C-7 (J. Gauthier, 1967 A. Belanger, 1968). 

The cyclization reactions discussed here either involve the intramolecular reaction of a donor group D with an acceptor group A or a cyclizing dimerization of two molecules with two terminal acceptors and two donors. A polymerization reaction will always compete with cyclization. For macrolides see p. 146 and p. 319 — 329. 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

Phenolic oxygen participates in facile oxypalladation. The intramolecular reaction of 2-hydroxychalcone (105) produces the flavone 106[127]. The ben-zofuran 107 is formed from 2-allyIphenol by exo cyclization with Pd(OAc)2, but benzopyran 108 is obtained by endo cyclization with PdChf S], Normal cyclization takes place to form the furan 109 from 2-(l-phenylethenyl)phe-nol[129]. Benzofuran formation by this method has been utilized in the synthesis of aklavinione (110)[130]. 

The intramolecular reaction oF allcenes with various O and N functional groups offers useful synthetic methods for heterocycles[13,14,166]. The reaction of unsaturated carboxylic acids affords lactones by either exo- or endo-cyclization depending on the positions of the double bond. The reaction of sodium salts of the 3-alkenoic acid 143 and 4-alkenoic acid 144 with Li2PdCl4 affords mostly five-membcrcd lactones in 30-40% yields[167]. Both 5-hexe-noic acid (145) and 4-hexenoic acid (146) are converted to five- or six-mem-bered lactones depending on the solvents and bases[168]. Conjugated 2,4-pentadienoic acid (147) is cyclized with Li2PdCl4 to give 2-pyrone (148) in water[i69]. 

The isocoumarin 151 is prepared by the intramolecular reaction of 2-(2-propenyDbenzoic acid (149) with one equivalent of PdCbjMeCN) . However, the (Z)-phthalide 150 is obtained from the same acid with a catalytic amount of PdjOAc) under 1 atm of Oi in DMSO, alone is remarkably efficient in reoxidizing Pd(0) in DMSO. The isocoumarin 151 is obtained by the reaction of 2-(l-propenyl)benzoic acid (152) under the same conditions[4], 2-Vinylbenzoic acid (153) is also converted into the isocoumarin 154, but not to the five-membered lactone) 167,170],... 

Indene derivatives 264a and 264b are formed by the intramolecular reaction of 3-methyl-3-phenyl-l-butene (263a) and 3,3,3-triphenylpropylene (263b) [237]. Two phenyl groups are introduced into the /3-substituted -methylstyrene 265 to form the /3-substituted /3-diphenylmethylstyrene 267 via 266 in one step[238]. Allyl acetate reacts with benzene to give 3-phenylcinnamaldehyde (269) by acyl—O bond fission. The primary product 268 was obtained in a trace amount[239]. 

An efficient carboannulation proceeds by the reaction of vinylcyclopropane (135) or vinylcyclobutane with aryl halides. The multi-step reaction is explained by insertion of alkene, ring opening, diene formation, formation of the TT-allylpalladium 136 by the readdition of H—Pd—I, and its intramolecular reaction with the nucleophile to give the cyclized product 137[I08]. 

Intramolecular reactions with alkenes. While the intermolecular reaction is limited to unhindered alkenes, the intramolecular version permits the participation of even hindered substituted alkenes, and various cyclic compounds are prepared by the intramolecular Heck reaction. Particularly the... 

Various bicyclic and polycyclic compounds are produced by intramolecular reactions] 127]. In the syntheses of the decalin systems 157 [38] and 158 [128], cis ring Junctions are selectively generated. In the formation of 158, allyhc silyl ether remains intact. A bridged bicyclo[3.3. l]nonane ring 159 was constructed... 

The TT-allylpalladiLim complexes formed as intermediates in the reaction of 1,3-dienes are trapped by soft carbon nucleophiles such as malonate, cyanoacctate, and malononitrile[ 177-179). The reaction of (o-iodophenyl-methyl) malonate (261) with 1,4-cyclohexadiene is terminated by the capture of malonate via Pd migration to form 262. The intramolecular reaction of 263 generates Tr-allylpalladium, which is trapped by malononitrile to give 264. o-[odophenylmalonate (265) adds to 1,4-cyciohexadiene to form a Tr-allylpalladium intermediate via elimination of H—Pd—X and its readdition, which is trapped intramolecularly with malonate to form 266)176]. 

When allene derivatives are treated with aryl halides in the presence of Pd(0), the aryl group is introduced to the central carbon by insertion of one of the allenic bonds to form the 7r-allylpalladium intermediate 271, which is attacked further by amine to give the allylic amine 272. A good ligand for the reaction is dppe[182]. Intramolecular reaction of the 7-aminoallene 273 affords the pyrrolidine derivative 274[183]. 

Allenes also react with aryl and alkenyl halides, or triflates, and the 7r-allyl-palladium intermediates are trapped with carbon nucleophiles. The formation of 283 with malonate is an example[186]. The steroid skeleton 287 has been constructed by two-step reactions of allene with the enol trillate 284, followed by trapping with 2-methyl-l,3-cyclopentanedione (285) to give 286[187]. The inter- and intramolecular reactions of dimethyl 2,3-butenylmalonate (288) with iodobenzene afford the 3-cyclopentenedicarboxylate 289 as a main product) 188]. 

The novel intramolecular reaction of the alkenyl bromide with the terminal alkyne in 328, followed by intramolecular Diels-Alder reaction, afforded the highly strained dynemicin A structure 329 in one stepf237]. 

Intramolecular reaction can be used for polycyclization reaction[275]. In the so-called Pd-catalyzed cascade carbopalladation of the polyalkenyne 392, the first step is the oxidative addition to alkenyl iodide. Then the intramolecular alkyne insertion takes place twice, followed by the alkene insertion twice. The last step is the elimination of/3-hydrogen. In this way, the steroid skeleton 393 is constructed from the linear diynetriene 392(276]. 

In the presence of a double bond at a suitable position, the CO insertion is followed by alkene insertion. In the intramolecular reaction of 552, different products, 553 and 554, are obtained by the use of diflerent catalytic spe-cies[408,409]. Pd(dba)2 in the absence of Ph,P affords 554. PdCl2(Ph3P)3 affords the spiro p-keto ester 553. The carbonylation of o-methallylbenzyl chloride (555) produced the benzoannulated enol lactone 556 by CO, alkene. and CO insertions. In addition, the cyclobutanone derivative 558 was obtained as a byproduct via the cycloaddition of the ketene intermediate 557[4I0]. Another type of intramolecular enone formation is used for the formation of the heterocyclic compounds 559[4l I]. The carbonylation of the I-iodo-1,4-diene 560 produces the cyclopentenone 561 by CO. alkene. and CO insertions[409,4l2]. 

No intennolecular reaction of malonate or /3-keto esters with halides has been reported, but the intramolecular reaction of /3-diketones such as 790 and malonates proceeds smoothly[652,653]. Even the simple ketone 791 can be arylated or alkenylated intramolecularly. In this reaction, slow addition of a base is important to prevent alkyne formation from the vinyl iodide by elim-ination[654]. 

A Pd-cataly2ed reaction of amines with halides is expected, but actually little is known about the reaction. The CDE ring system of lavendamycin (805) has been constructed by the intramolecular reaction of aryl bromide with aniline derivative in 804, but 1.2 equiv, of Pd(Ph3P)4 is required[679]. 

As supporting evidence, rapid isomerization of the ds- and maui-Tr-allylpal-ladium complexes 27 and 28 is catalyzed by Pd(Ph3P)4 in THF even at -15 C to give a 45 55 equilibrium mixture from either 27 or 28[29-31].. Actually, in the intramolecular reaction of soft nucleophiles of 29 and 30, a trans-ds mi.xttire (31 and 32) (1 1) was obtained from /raiw-allylic acetate 29. On the... 

The reaction of vinyloxiranes with malonate proceeds regio- and stereose-lectively. The reaction has been utilized for the introduction of a 15-hydroxy group in a steroid related to oogoniol (265)(156]. The oxirane 264 is the J-form and the attack of Pd(0) takes place from the o-side by inversion. Then the nucleophile comes from the /i-side. Thus overall reaction is sT -StM2 type, in the intramolecular reaction, the stereochemical information is transmitted to the newly formed stereogenic center. Thus the formation of the six-membered ring lactone 267 from 266 proceeded with overall retention of the stereochemistry, and was employed to control the stereochemistry of C-15 in the prostaglandin 268[157]. The method has also been employed to create the butenolide... 

Intramolecular reaction of the allenyl carbamate 5 in the presence of a large excess of allylic chloride catalyzed by Pdi(dba)3 or PdCl2(PhCN)2 affords the substituted oxazolidin-2-one 6. Since the reaction is catalyzed by both Pd(II) and Pd(0), its mechanism is not dear[3]. 

Butyrolactones are prepared by intramolecular reaction of haloallylic 2-alkynoates. The a-chloromethylenebutyrolactone 301 is prepared by the intramolecular reaction of300[150,151]. 4 -Hydroxy-2 -alkenyl 2-alkynoates can be used instead of haloallylic 2-alkynoates, and in this reaction, Pd(II) is regenerated by elimination of the hydroxy group[152]. As a related reaction, the q-(chloromethylene)-7-butyrolactone 304 is obtained from the cinnamyl 2-alkynoate 302 in the presence of LiCl and CuCbflSS]. Isohinokinin (305) has been synthesized by this reaction[l 54]. The reaction is explained by chloro-palladation of the triple bond, followed by intramolecular alkene insertion to generate the alkylpalladium chloride 303. Then PdCb is regenerated by attack of CuCb on the alkylpalladium bond as a key step in the catalytic reaction. 

The ring nitrogen can be involved in intramolecular reactions on carbonyl carbon as exemplified by the preparation of 6,7-dimethoxy-4-methyl-10,ll-thiopega-2,9-diene (72) (Scheme 51) (228). 

Preformed Carbocationic Intermediates. Propargyl cations stabilized by hexacarbonyl dicobalt have been used to effect Friedel-Crafts alkylation of electron-rich aromatics, such as anisole, /V, /V- dim ethyl a n il in e and 1,2,4,-trimethoxybenzene (24). Intramolecular reactions have been found to be regio and stereo-selective, and have been used ia the preparatioa of derivatives of 9JT- uoreaes and dibenzofurans (25). 

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