Cyclization base mediated

Garratt—Braverman cyclization (base-mediated rearrangement of bis-propargyl sulfones via bis-aUenes generated in situ), a powerful tool for C—C bond formation 12SL2582. 

Mesylates and tosylates may be used as variants of the 0-sulfate ester. For instance, 55% of aziridine 7 was obtained from base-mediated cyclization of amino mesylate 6. In comparison, the classic Wenker protocol only gave 3% of 7. In another instance, A-tosyl amino alcohol 8 was tosylated to give 9, which was transformed to aziridine 10 in 64% yield, along with 29% of the P-elimination product due to the presence of the ester moiety. Likewise, aziridine 12 was assembled from tosylate 11 in two steps and 60% yield. ... 

A one pot synthesis of isoxazolines 78a-f involves base mediated 1,4-addition of malonate or alcohol 76 possessing an allylic substituent, conversion of the resulting nitronate to the a-chloroaldoxime (hydroxymoyl chloride 77) and its subsequent dehydrohalogenation to the nitrile oxide intermediate which cyclizes to isoxazoline 78 (Eq. 7, Table 6) [32]. 

Knochel and co-workers employed the base-mediated cyclization of 2,6-diamino-3,5-dialkynylpyridines in the synthesis of bis-pyrrolopyridine 95 from bis-acetylene 94 (Equation 21) <2003PS(178)1781, 2003T1571>. 

Base-mediated intramolecular cyclization of an amino-substituted triazole onto the chloropyrazole of compound 257 with loss of HG1 generates the central pyrimidine ring of 258 (Equation 70) <2004JCM50, 2004SC151>. 

The synthesis of a series of thiazolo[2,3-c][l,2,4]triazole derivative 33 has been approached by base-mediated intramolecular cyclization of bromide 349 or acid-promoted ring closure of alcohol 350, obtained from pyrazinoyl-dithiocarbazate 348 (Scheme 33) <2004PS(179)2519>. 

In the improved synthesis of Ifetroban described above, environmental concerns due to special handling of copper bromide waste and hazards associated with hexa-methylene tetramine (HMT) on manufacturing scale led to further perfection of the synthesis. Mechanistic considerations suggested that an oxidized form of aminoamide B (Scheme 4) would eliminate the necessity for a late-stage copper-mediated oxidation. This was indeed accomplished. The cyclization-elimination sequence was initiated by a Lewis acid and completed by base-mediated elimination to afford the Ifetroban penultimate. In addition to eliminating the need for copper bromide and HMT, this modification helped to reduce the cost of the product by an additional 15%. 

Various more or less efficient methods have been reported for the synthesis of 2-(l-ami-noalkyl)thiazole-4-carboxylic acids and their suitably protected derivatives. 237,539,541,558-568 Optimal conditions must be selected in these syntheses to prevent racemization at the chiral aminoalkyl moiety, e.g. when applying a modified Hantzsch synthesis 559 racemization has been observed to occur at the level of the starting Na-protected amino acid thioamide as well as in the base-mediated dehydration step of the intermediate hydroxydihydrothiazoles. 558 The 2-(aminoalkyl)thiazole-4-carboxylic acids are incorporated into the linear precursors by standard procedures of peptide synthesis, 237,514,529,539,552,555,558,564,569 and cyclization is pref-... 

Racemic morpholine-3-carboxylic acid (4-oxapipecolic acid, 18) is prepared by a multistep synthesis, starting from 3-methoxymorpholine 205 It can, however, be obtained as optically pure (3S)-morpholine-3-carboxylic acid (l-4-oxapipecolic acid) by base-mediated cyclization of 0(2-chloroethyl)-L-serine.[253] Similarly, (4S)-tetrahydro-2//-1, 3-oxazine-4-carboxylic acid (L-5-oxapipecolic acid, 19) is obtained from L-homoserine by reaction with aqueous formaldehyde under alkaline conditions 173 ... 

Substituted 1,2,3-triazole 1-oxide 448 can be prepared by N-oxidation of 1-substituted 1,2,3-triazoles 457, by N-alkylation of 1-hydroxy-1,2,3-triazoles 443, by cyclization of triazene 1-oxides 460, or by rearrangement of 2-substituted 1,2,3-triazole 1-oxides 445 (R=PMB). Finally, base-mediated ring opening of pyrimidinediones 463 offers a route to 464. 

Radical cyclizations based on tin mediation present an additional method for effecting intramolecular additions to unsaturated sugar derivatives, the processes commonly occurring with both regio- and stereo-specificity. 

Resin-based chemistry has been used to construct 480 from 481 by use of boron trifluoride to mediate both the cyclization and cleavage steps <1999AGE1121 >. When the monosaccharide was bound to the polystyrene resin (Merrifield and MPP type) by an alkylsulfonyl linker 482 and cyclization was mediated by 2- r/-butylimino-2-diethylamino-l,3-dimethylperhydro-l,3,2-diazaphosphorine, the reaction had low stereoselectivity and the products included tricyclic oxetanes and oxiranes <2004EJ04177>. The Mitsunobu reaction was used to obtain intramolecular N-alkylation of 483 and formation of 484 <2005AGE3732>. 

Conversion to benzazepine was achieved under acidic conditions via hydrogenation in alcoholic solvents to form 25, which did not require isolation. Intermediate 25 was directly cyclized under basic conditions to give crystalline lactam 26. The base-mediated ring closure proceeded from the cis/trans mixture of 25 by epimerization of the benzylic methine permitting formation of the cyclic amide from the cis isomer. Finally, conversion of 26 to the desired benzazepine (8) was accomplished by in situ borane reduction and 8 was isolated as the tosylate salt in 81% yield. 

The asymmetric synthesis of 4-alkyl-4-carboxy-2-azetidinones 18 has been achieved through base-mediated intramolecular cyclization of the corresponding Af-a-chloroacetyl derivatives bearing (+)- or (-)-10-(W,A,-dicyclohexylsulfamoyl)isobomeol as chiral auxiliary (ee up to 82%) <02JOC3953> <02H501>. 

Kopecky s synthesis of trimethyldioxetane employed the base-mediated dehydrohalogenation of 2-methyl-2-hydroperoxy-3-bromobutane. Subsequently, this type of eliminative cyclization (14) has been applied to the preparation of scores of dioxetanes. Additionally, many dioxetanes have been prepared by the addition of singlet oxygen to electron-rich olefins which do not possess allylic hydrogens (15), a method discovered first by Bartlett and Schaap... 

Base-induced (KH or /-BuOK) cyclizations of o-alkynylanilines were utilized to prepare 2-substituted indoles and poly-substituted indoles. For example, treatment of alkynes 86 with KH gave the corresponding indoles 87 <03T1571>. Similar base-mediated cyclizations and related indole syntheses were utilized to prepare indole inhibitors of 5 -inosine monophosphate dehydrogenase <03BMCL1273>. Moreover, base-induced cyclizations of arylacetonitriles with oxalic acid bis(imidoyl)chlorides provide a route to 2-alkylidene-3-iminoindoles <03CEJ3951>. 

The DAST-mediated cyclodehydration gives higher yields of DBFOX than the original base-mediated cyclization. 

Aspartic acid P-esters are incompatible with this group since cyclization to aspartimide occurs during the base-mediated deprotection. Even aspartic acid P-tert-butyl ester residues undergo this reaction with the related a P transpeptidation (see Section 2.2.2). Similarly, with C-terminal asparagine tert-butyl ester rapid succinimide formation was ob-... 

N -Protection as allyl carbamate is used generally only for specific synthetic purposes where acid- or base-mediated deprotection procedures must be avoided or reduced to a minimal extent as in the case in the synthesis of glyco- and phosphopeptides (see Sections 6.3 and 6.5). Otherwise the orthogonality of this type of amino protection has been mainly exploited in side-chain protection to allow for selective chemistry such as selective acylations, e.g. cyclizations, to be performed on protected peptides in solution or in the resin-bound state (see Section 4.3.2.3.4). An additional interesting application of the Aloe group is the one-pot deprotection and acylation with carboxy components resistant to the paUadium(0)-catalyzed allyl cleavage by hydrostannolysis as reported in Section 4.3.2.3.4.P 1... 

Because Michael-type reactions are among the most useful base-mediated cyclizations, the first examples presented in this chapter center around this chemistry. Thus, utilizing Wittig methodology, Vyplel et al. [37] prepared the hydroxyolefin (shown in Scheme 7.93) from the starting protected glucosamine. Treatment of this intermediate species with DBU effected cyclization of the 5-hydroxy group to the unsaturated ester in a Michael fashion. Notably, the cyclization provided the a anomer in 43% yield, with an additional 7% accounted for in the isolation of the (3 anomer. 

Unlike base-mediated cyclizations, halocyclizations do not depend on the presence of Michael acceptors. As shown in Scheme 7.94, Armstrong and Teegarden [234] treated a hydroxyolefin (derived from a Wittig reaction applied to a protected arabinose) with A-bromosuccinimide and catalytic bromine to activate the illustrated cyclization. The reaction took place through an intermediate bromonium ion, providing a 52% yield of the (3 anomer. This observation is consistent with the preference for a anomers observed in base-mediated cyclizations. Moreover, the isolation of a bromo-substituted C-glycoside allows the preparation of new and novel structures. This chemistry was further adapted to the use of iodine instead of bromine [235]. 

Although technically ether formations, the displacement of halides by hydroxyl groups differs from the examples presented above in that these reactions are base mediated. As such, under these conditions, C-glycosidations complement the previously described cyclization strategies given that they allow reactions with acid sensitive substrates. As shown in Scheme 7.100, Schmid and Whitesides [244] used this approach in the preparation of C-furanosides. Specifically, the illustrated... 

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