Ring closure intramolecular alkylation

Oxidative Ring Closure Reactions 4.03.4.1.1 C—N bond formation N—N bond formation C—S bond formation N—S bond formation O—C bond formation O—N bond formation S—S, S—Se and Se—Se bond formation Electrophilic Ring Closures via Acylium Ions and Related Intermediates Ring Closures via Intramolecular Alkylations... 

An unusual one-pot intramolecular sulfoxide alkylation-elimination reaction was found by Gibson et al. <2001SL712>. These authors found that treatment of 459 with potassium bis-trimethylsilylamide resulted in a ring closure to 460 in acceptable yield. Furthermore, Batori and Messmer found an effective method for preparation of [l,2,3]triazolo[l,5- ]pyrimidinium salts <1994JHC1041> oxidative cyclization of hydrazones 461 by 2,4,4,6-tetrabromo-2,5-cyclohexadienone gave rise to the quaternary salts 462. Under certain reaction conditions, the formation of 6-bromo-salts 462 (R6 = Br) was also experienced. As neither the starting compound nor the quaternary triazolopyridinium salt underwent bromination in this position, the authors assumed that this bromination process occurred on one of the intermediates in the course of the above-mentioned cyclization reaction. 

A rather different allene cyclization that takes place in tandem with an alkylative process has been described by Trost and Urabe [66] (Eq. 13.52). Exposure of ketoal-lene 169 to divinylmethylaluminum 170 in dichloromethane solution leads to 171 in 60% yield. The mechanism of this alkylative cyclization involves complexation of the Lewis acidic aluminum to the carbonyl oxygen atom, followed by ring closure, leading to zwitterion 172. Intramolecular transfer of a vinyl group from aluminum to carbon completes the process. 

The Delft synthesis makes use of an acid-catalyzed ring closure - in fact an intramolecular aromatic alkylation - of a l-(3,5-dihydroxy-4-methoxybenzyl) isoquinoline derivative that is prepared starting from (natural) gallic acid. One of the hydroxyl groups is removed via a Pd/ C hydrogenation of the benzyl ether. Other catalytic steps play an important role some steps were improved recently [27]. The crucial step in the Rice synthesis makes use of a l-(2-bromo-5-hydroxy-4-methoxybenzyl)isoquinoline derivative that is also cyclized in an acid-catalyzed ring closure to the morphinan skeleton, followed by catalytic removal of the bromo substituent (Scheme 5.8). 

A common feature of any cyclization reaction is that a new intramolecular C—C bond is produced that would not have been formed in the absence of the catalyst. Those reactions in which one ring closure step is sufficient to explain the formation of a given cyclic product will be called simple cyclization processes, although their mechanism is, as a rule, complex. We shall distinguish those cases in which any additional skeletal rearrangement step(s) is (are) required to explain the process. Some specific varieties of hydrocarbon ring closure processes are not included. A recent excellent review deals with the formation of a second ring in an alkyl-substituted aromatic compound (12). Dehydrocyclodimerization reactions have also to be omitted—all the more since it is doubtful whether a metallic function itself is able to catalyze this process (13). 

N-Alkyl isoindolo[2,l-fc][2,4]benzodiazepines 190 (R = alkyl. Scheme 38, Section 3.1.1.2) are synthesized by an intramolecular N-acyliminium ion-amide reaction (1997TL2985, 1998T1497). Isothiocyanates 23 undergo under basic conditions in DMF ring closure by an intramolecular substitution between N1 of the pyrrole ring and isothiocyanate group to afford benzo[/]pyrrolo[l,2-c] [l,3]diazepine-5-thiones 25 (Scheme 2, Section 2.1.1.1 (2005BMCL3220)). 

Interest in the total synthesis of the Aspergillus terreus derived quadrone fi06), an antitumor agent has been very intense. Success was first realized in Danishefsky s laboratory Once 601 was reached, its sidechain was elaborated and ring closure effected (Scheme LII). Condensation of 602 with 1-tert-butoxy-l-tcrt-butyl-dimethylsiloxyethylene in the presence of titanium tetrachloride and subsequent desilylation resulted in introduction of an angular acetic acid moiety. The two sidechains were next connected by intramolecular alkylation and the resulting keto add was subjected to selenenylation in order to produce 603. The a, P-unsaturated double bond was used to force enolization to the a position. Indeed, 604 was... 

A -Hydroxy derivatives can be alkylated and acylated on the oxygen atom, and this can also be performed intramolecularly to give ring-closure products such as the oxazino[3,2-A]quinazolinedione 607 <2006RJ0382>. 

In addition, we were able to extend the tandem hetero Michael addition/a-ester-enolate alkylation protocol by an intramolecular variant via a Michael-initiated ring closure (MIRC) reaction leading to diastereo- and enantiomerically pure trans-configured 2-amino-cycloalkanoic acids 30 (Scheme 1.1.7) [14c,d]. 

A recent development in the synthesis of 3//-3-benzazepin-2-ones has been the photocyc-lization of A-(chloroacetyl)phenethylamines (Scheme 25). Ring closure is by homolysis of the alkyl halide followed by intramolecular coupling of the alkyl radical with an aromatic radical cation. Yields are good, especially with a stabilizing electron-donating group (MeO, NMe2) at the position meta to the ethylamino function (i.e. ortho or para to the site of cyclization). Isomeric benzazepinones are normally obtained (Scheme 25) with meta-substituted phenethylamines (80H(14)ll). 

Benzoxepins are frequently synthesized by cyclization of alkyl aryl or diaryl ether precursors. An intramolecular Wittig reaction (equation 48) is used to provide the ring closure step in the synthesis of 1-benzoxepin (28) (68JOC2591). An internuclear cyclization reaction of an aromatic sulfonyl chloride (equation 49) occurred upon heating (250 °C) in the presence of a copper chloride catalyst to yield tribenz[6,d,/]oxepin (175). The analogous thiepin (see equation 71) may also be synthesized by this route (65T1299). 

This then was the first report of a compound in which alkyl C—H bond activation by a transition metal had occurred. In the solid state, this equilibrium is also in favor of the hydrido complex (V), and its crystal structure has recently been determined (15). It shows compound V to be a dimer (VI), the oxidative addition of the methyl group of a ligand on each ruthenium atom being to a second ruthenium atom. Presumably one reason why this occurs is because the product of intramolecular ring closure would contain a highly strained three-membered Ru—P—C ring (i.e., in monomer V). 

Koenigs method for quinuclidine ring closure was applied by Rubtsov90,91 and Grob 92,93 to the intramolecular alkylation of a-halogeno acids and esters of piperidines. Rubtsov and Dorokhova 90 developed a simple five-step method for the synthesis of quinuclidine-2-carboxylic acid (39). 

Intramolecular alkylation of a lithiated species has been exploited in the synthesis of [1.1.0]- and [1. l.l]-propellanes (equation 45).143-145 In what appears to be a related reaction, the bis(dibromocarbene) adduct (11) on treatment with methyllithium undergoes a ring closure by 1,6-elimination, presumably via a four-center transition state, to give (12 equation 46), which was subsequently converted to a bis(ho-mobenzene).146... 

The products arising from the reaction of 431 with the alkyl-substituted silenes 149 and 150 suggest that the reaction occurs by a radical pathway, initiated by a homolytic Si—C bond cleavage of 431 and subsequent Si—Si bond formation giving the biradical 434. Intramolecular disproportionation of 434 gives 435, while 436 and 437 are the results of ring closure reactions without or with expulsion of tetramethylethene, respectively (equation 139)181. 

Electrophilic ring closure of aryl-substituted compounds such as alkenes, halides, alcohols, and carbonyl compounds called cyclialkylation can be induced by conventional Friedel-Crafts catalysts309 and by superacids. Examples are also known in which an intermolecular alkylation step is followed by intramolecular alkylation of the intermediate to furnish a cyclic product. 

The intramolecular alkylation of a BOC-protected aniline by an cr-bromo amide using NaH in DMF, depicted in Scheme 29, provided an example of a type a ring closure to l,4-benzodiazepin-3-ones, a straightforward and effective procedure that, surprisingly, has not been more broadly exploited <2005EJ01590>. 

The intramolecular alkylation of an aryl amide by an activated bromide, readily available by bromination of a malonamide methylene with pyridinium tribromide in the substrate depicted in Scheme 39, provided an example of a type c ring closure to furnish 3-carboxymethyl-l,4-benzodiazepin-2,5-diones <20060BC510, 2002H(56)1501, 1999JOC2914>. 

---