N-Alkylation intramolecular

The usefulness of this reaction for the preparation of heterocycles under mild conditions became apparent in 1978, when chemists from Merck, Sharp Dohme reported the synthesis of bicyclic 3-lactams by intramolecular carbene N-H insertion [1179]. Intramolecular N-alkylation of P-lactams by carbene complexes is one of the best methods for preparation of this important class of antibiotic and many P-lactam derivatives have been prepared using this methodology [1180 -1186] (Table 4.11). Intramolecular N-H insertion can also be used to alkylate amines [1187-1189], y-lactams [1190], and carbamates [1191-1193] (Table 4.11). 

Intramolecular N-alkylation of tertiary amines, followed by Stevens rearrangement, enables rapid preparation of elaborate polycyclic structures [1235-1238]. Illustrative examples are given in Table 4.16. 

Niridazole Niridazole, l-(5-nitro-2-thiazolyl)-2-imidazolidinone (38.1.11), is made by reacting 2-amino-5-nitrothiazol with 2-chloroethylisocyanate to make the disubstituted urea (38.1.10). Heating this compound results in an intramolecular N-alkylation reaction to form the desired imidazolidine derivative, niridazole [7-11]. 

Among them are found the naturally occurring 1-deoxynojirimycin (DNJ) and 1-deoxymannojirimycin (DMJ) [96]. Practical syntheses of DNJ and DMJ start from L-gulono-1,4-lactone (20b) and o-mannono-1,4-lactone (74), respectively [97]. Key intermediates are 2,6-dibromo-2,6-dideoxy-D-alditol derivatives 75a and 75b obtained by 2,6-dibromination of the starting lactones, followed by reduction with NaBH4 [98, 99]. Then a five-step sequence involving selective partial protection, introduction of an amine functionality, and intramolecular N-alkylation, lead to DNJ and DMJ, respectively (Scheme 22). 

Treatment of 7-chloroamine 363 with potassium /i t/-butoxide in refluxing THE gave rise to a mixture of (Z-tert-butyl)-5,5-dimethyl-5,6-dihydro-4f/-l,3-oxazine 366 and 1-pivaloylazetidine 367 (Scheme 67). The heterocycles 366 and 367 were formed through generation of the Favorskii intermediate 364 by dehydrocyanation, which was followed by opening of the cyclopropylideneamine by /r-rt-butoxide with the subsequent loss of isobutene and a subsequent intramolecular N-alkylation or O-alkylation of the amide anion 365 <1999EJ0239>. 

When the desired product is a tetrahydrooxazin-3-one, it is sometimes favorable for the amide bond formation to be the final step. Scheme 31 shows two ways to form the amide linkage in 282 starting from 280 or 281 <1999EJ01967> and formation of 284 <2005WO16899> by intramolecular N-alkylation of the amine function in 283. 

Alcohol 34 has been used in an intramolecular N-alkylation (Equation 3) <2001TL5941>. Treatment of 34 with refluxing thionyl chloride in dichloromethane gave tricyclic 35 as the HCl salt. 

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

Golebiowski et al. reported the solid-phase [92] and the solution-phase [93] syntheses of bycyclic diketopiperazines which were of great interest because their conformation was similar to the type-1 /i-turn motif. A Merrifield hydroxymethyl resin was esterified with a-N-Boc-fi-N-Fmoc-L-diaminopropionic acid and then mono-deprotected at the />-N with piperidine. Ugi-4CR of the resulting resin-bound amine gave the resin-bound adducts 168. Subsequent N-Boc deprotection and intramolecular N-alkylation afforded the ketopiperazines 169. The diketopiperazines 170 were formed via N-Boc amino acid coupling followed by N-Boc deprotection... 

Intramolecular N-alkylation under phase-transfer conditions (PTCs) of 236 and 237 having the triisopropylbenze-nesulfonyl (TIBS) protecting groups give the corresponding clavams 238 where R = a-H and /3-H, respectively... 

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>. 

Synthesis, structure and conformational behavior of cyclophanes are of interest. Synthesis of a novel chiral cyclophane consisting of indole as one of the core units was achieved [198]. The first bridge of the cyclophane 273 is formed by a conjugate addition of indole (2) to the unsaturated ketone 269. An intramolecular N-alkylation reaction of 271 resulted in the formation of... 

A related intramolecular N-alkylation leading to saturated nitrogen heterocycles 99 can proceed via dehydration of intermediates 98 (Eq. 39) [96]. Unsaturated nitrogen heterocycles such as pyrroles [97], indoles [98], benzo-azoles [99], 2,3-dihydroimidazol-2-ones [100], and imidazo[l,2-a]pyridines [101] were obtained through similar cyclocondensation reactions. Interesting ruthenium-catalyzed syntheses of quinolines have been achieved by means of cyclocondensations of aniline derivatives with propanediols, aminoalcohols, or... 

A convenient intramolecular N-alkylation of the functionalized indole 62 produced the 1,4-diazocine 63 in high yield (Equation 8) <2004BML3925>. 

Eight-membered A,iV -protected cyclic sulfonylamide 89, bearing two different protecting groups, was demonstrated as useful intermediate for preparation of pseudopeptides. Synthesis of 89 was carried out in two steps by an intermolecular Mitsunobu reaction followed by intramolecular N-alkylation (Scheme 20 <2003T6051>). 

Tertiary Mannich bases having a halogen atom in position 4 with respect to the amino group (Fig. 127) can give cyclic products by intramolecular N-alkylation, with formation of the heterocyclic quaternary salts 330, as shown by the N-Mannich bases of chloroacctohydrazidc and by some brominated O-Mannich bases. ... 

As with the mitomycins, general routes to the synthesis of FR900482 and analogs have evolved. A very straightforward approach is the formation of the aziridine ring late in the synthesis using an intramolecular N-alkylation. A second is the incorporation of an intact monocyclic aziridine as part of the formation of the tricyclic ring system. 

During the endgame of the total synthesis of the stemona alkaloid (-)-stenine, Y. Morimoto and co-workers utilized the Finkelstein reaction to prepare a primary alkyl iodide from a primary alkyl mesylate. The mesylate was prepared from the corresponding primary alcohol with MsCI/EtsN. The resulting primary alkyl iodide was used in the subsequent intramolecular N-alkylation to construct the final perhydroazepine C-ring of the natural product. 

Another synthesis of a quaternary salt (8) was developed by Meyer and Sapianchiay for the purpose of studying the steric course of formation of the pyrrolizidine system.9 Photolysis of the N-chloroamine (9) in a Hofmann-Loeffler-Freytag reaction [Eq. (4)], gave an intermediate that yielded the pyrrolizidine salt (8) in an intramolecular N-alkylation. The product was the cis-isomer, reflecting the greater degree of strain in the trans-fusion of two five-membered rings. 

The carbapenam (276) is formed with high diastereoselectivity and the regioselectivity of the cyclization can be controlled either by varying the initial concentration of the bromide (275) or by varying the cyclization conditions (thermal or photochemical). An alternative approach to the carbapenam derivative (279) has been described by Dumas et al. which utilizes an efficient base-catalysed intramolecular N-alkylation of the iodide (278).150 Interestingly, attempted cyclization of the epimeric (at C-3) iodide was unsuccessful. 

JA5469>. Intramolecular N-alkylation gives pyrrolopyrazine-l,4-dione (254) (Equation... 

Intramolecular N-alkylation of 3-allylthio-5-phenyl-l,2,4-triazine 3 has been found to occur on treatment with bromine, and it is directed exclusively at N-2, thus giving 3-bromomethyl-7-phenyl-2,3-dihydrothiazolo[3,2-3]-l,2,4-triazinium bromide 4 (Scheme 6) <1997RJO1033>. 

Mizuno et al. reported an interesting example of an intramolecular N-alkylation of IbP 3-)3-D-ribofuranosyl-3H-IbP 5 -tosylate 265 refluxed in acetone afforded cyclic salt 266 (63CPB265). 

The final B ring formation by intramolecular N-alkylation requires a C2 side chain attached to the A ring of the C5-spiroisoquinoIine educt, e.g. 133. This has been similarly obtained as the related educt 119 (Scheme 16) by reaction of the lithiated phenethyl derivative 131 with the N-protected quinone imide ketal 132. After deprotection the crude amine undergoes cyclization to form the 15-0-methylerysodienone (134) in 80% yield (77) (Scheme 18). 

Alkaloids containing a 2,6-dialkylated piperidine ring are found abundantly in nature and the Prosopis alkaloids, one of the subgroups of these alkaloids, could possess local anesthetic activity. (-)-Deoxoprosopinine and (—)-deoxoprosophyUine were enantiospecilically and stereoselectively synthesized from methyl 3,4-dideoxy-a-D-eryt/tro-hexopyranoside. The key intermediate 299 was prepared by standard procedures and the dialkylated piperidine ring was formed in the key step by Pd(0)-catalyzed intramolecular N-alkylation of 299. The cyclization proceeded at room temperature when 299 was treated with NaH in THF in the presence of 1 equiv of n-BujNI and a catalytic amount of Pd(PPh3)4 (Scheme 75). 

The Keck group described an approach to the pyrrolizidine alkaloids that revolved around acylnitroso Diels-Alder chemistry. The plan, outlined within the context of an approach to heliotridine (38), was to once again use an intramolecular N-alkylation to construct the N4-C3 bond. N-Alkylation substrate 39 was to be prepared by reduction of the N-O bond of 40, which was to result from an intramolecular cycloaddition of 41. It was hoped that the C7 substituent might induce relative stereochemistry at 07 by occupying a site on the convex face of the incipient azaoxabicyclo[4.3.0]nonane ring system in the cycloaddition transition state. Note that the cycloaddition of 41 establishes the olefin geometry needed to support the intramolecular N-alkylation. 

N- ondensed heterocyclics from alcohols by intramolecular N-alkylation... 

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