Unsubstituted lactam

Non-enolizable aldehydes are transformed into N-trimethylsilylaldimines on treatment with lithium hexamethyldisilazide (22) such imines provide valuable routes to N-unsubstituted / -lactams ... 

Cydizations proceeding via radicals are, apparently, better suited to the preparation of N-unsubstituted lactams (Scheme 9.11). Nevertheless, in this type of cydiza-tion also the formation of N-substituted lactams proceeds more rapidly and more cleanly. 

In the polymerization of unsubstituted lactams, propagation proceeds mainly by the activated monomer mechanism ... 

Lactams (7, 335). Cyclization of /3-halopropionamides to N-alkyl unsubstituted -lactams is usually not an attractive method because of competing /3-elimination. However, dilution favors the desired intramolecular displacements. Under favorable conditions this route can be useful. /3-Bromo amides are cyclized in higher yields than /3- chloro amides. The structure of the R group on nitrogen also can influence the course of the reaction. ... 

Similarly, the unsaturated /V-benzyl lactams 7 were treated with electrophiles to give the bicyclic lactams 8. The stereochemistry was dependent on the ring size and the presence of substituents at C-3235 236. The trans-adduct 8 was always obtained from the nine-membered lactams 7 (n = 0), but from the homologous lactams (n = 1) the configuration of 8 was dependent on the substitution at C-3. In fact, the unsubstituted lactam gave c7.v-8, but 3,3-dichloro-7 gave trans-8, due to 1,3-diaxial-type interactions between X and R236. 

Fig. 2. Effect of ring size on the heat of polymerization of unsubstituted lactams (CH2) CONH- [10, 27, 33, 35, 37-39, 42, 43],...

In the polymerization initiated with strong acids under anhydrous conditions the major part of monomer is incorporated into the polymer via highly reactive intermediates [243]. In the presence of strong acids, protonation of -substituted lactams can occur both at the oxygen and nitrogen (see Section 3). Similarly as with the unsubstituted lactams (Section 5.1), the iV-protonated form (XXXI) resulting from the equilibrium... 

Dissolving metal ammonia reduction (Na/NH3) of (20) gives the A-unsubstituted lactam in 75% yield, which is a key intermediate in the synthesis of the benzomorphinan family of analgesics... 

Indium enolates, prepared conveniently by transmetalation of hfhium enolates with IriCl j, react wifh aldehydes to give fhe corresponding -hydroxy esters [80]. Ultrasound irradiation promotes fhe Reformatsky reaction of aldehydes and ethyl bromoacetate wifh indium [81]. Indium-mediated Reformatsky reaction of phenyl a-bromoalkanoates wifh ketones or aldehydes gives di-, tri-, and tetrasubstituted -lactones (Scheme 8.57) [82]. Indium-mediated reaction of imines with ethyl bromoacetate gives 3-unsubstituted -lactams (Scheme 8.58) [83]. An indium-Refor-matsky reagent prepared from 2-(chlorodifluoroacetyl)furan couples with aldehydes (Scheme 8.59) [84]. 

Alkylation of pyrazol-3-ones usually occurs not only on side-chain substituents such as primary amino groups but also on the nitrogen atom of the unsubstituted lactam group. Alkylation can also occur on a stabilized carbanion generated from a methyl group by a strong base. 

Unsubstituted lactams polymerize cationically with high activation energies, at elevated temperatures (about 200 °C). With increasing temperature the contribution of termination reactions (i.e. formation of non-reactive amidine end-groups) also increases, which leads to the incomplete conversion. 

Cationic polymerization proceeds faster with strained unsubstituted lactams 50% conversion is reached in bulk polymerization with 1 % of HC1 at 180 °C after 1 hour with 9-membered lactam and after more than 2 weeks with the less strained 13-membered lactam. With changing the ring size of lactams (e.g. 9 - 13) not only the ring strain is changed (AAHP = 7 kcal mol-1) but also their basicities and dielectric constant of the medium (Ae = 17)3). 

Polymerization of N-alkyl lactams is thermodynamically less favorable than that of the unsubstituted lactams of the same ring size (e.g. N-methyl CLM cannot homo-... 

Unsaturated AT-chlorosulfonyl-jft-lactams are generally unstable and readily rearrange to the product of formal 1,4-addition. Thus, the reaction of 1,3-cyclohexadiene with CSI at room temperature affords a quantitative yield of adduct 150. Hydrolysis of 150 with benzenethiol in the presence of pyridine gives 151 in 67% yield. When the reaction mixture of CSI and 1,3-cyclohexadiene was refluxed in chloroform, 152 was formed in 90% yield as a viscous oil. Hydrolysis of 152 with aqueous NaOH gave iV-unsubstituted lactams in 35% yield. 2-Azabicyclo[2.2.2]octene (153) can be conveniently prepared by reduction of 152 with LiAlH4 after hydrolysis (equation 81)76. 

An alternative approach to the p-lactam ring system uses the cycloaddition of an alkene with an isocyanate such as chlorosulfonyl isocyanate (0=C= N—SOiCl). For example, reaction of cyclopentadiene with chlorosulfonyl isocyanate gave the p-lactam 183 (3.121). The A-unsubstituted -lactam is formed under these conditions owing to the ease of removal of the SO2CI group. The regioselectivity can be explained by combination of the more electron-rich end of the alkene with the electron-dehcient carbon atom of the isocyanate. 

Thionation of Lactams. The thionation of TV-substituted lactams with 1 in toluene/pyridine provides the corresponding thiolactams, e.g., TV-methylp)rrolidin-2-one (13) is transformed into TV-methylpyrrolidine-2-thione (14) (eq 6). The observed selectivity in the case of lactams is similar to that of amides the reaction of TV-unsubstituted lactams with 1 is sluggish, i.e., the product pyrrolidine-2-thione is formed in very low yield. 

The parentheses designate a low-intensity shoulder on the main peak of the spectrum for the Cr(III) complexes. Shoulders appeared for the Ni(II) complexes of the unsubstituted lactams at a higher frequency than the second band, but were too low in intensity and too broad to be measured accurately. For the Ni(II) complexes the calculated values for of the second band agree very well with the experimental values. 

The phenol frequency shifts for the methyl lactams give a donor order of 5- < 6- 7-membered ring. This is the same order given by the Dq values for the unsubstituted lactam complexes of nickelfll). " ... 

Figure 8 Heat of polymerization of unsubstituted lactams as a function of their size (from data in Table 5).

Figure 9 Entropy of polymerization as a function of ring size for unsubstituted lactams °) and cycloalkanes ( ). Reproduced from Sekiguchi, H. In Ring-Opening Polymerizations, Ivin, K. J. Saegusa, T., Eds. Elsevier London, UK, 1984 Vol. 2, Chapter 12, p 809. ...

Figure 12 Equilibrium polymer content for methyl-CL isomers at 250 °C as a function of the position of the methyl substituent. The dashed line represents the unsubstituted lactam. Reproduced from Sebenda, J. In Comprehensive Chemical Kinetics, Bamford, C. H. Tipper, C. F. H., Eds. Elsevier Amsterdam, The Netherlands, 1976 Vol. 15, Chapter 6, p 379. ...

As compared to the addolytic, aminolytic, and hydrolytic routes, entailing the same reactions involved for unsuhstituted lactams (excluding amidine formation), the polymerization initiated by protic acids, such as HCl, differs for the most part. The most relevant aspeas characterizing the cationic polymerization of N-substituted lactams are, as said already, the absence of the detrimental formation of amidines and a much simpler mechanism compared to that pertaining to N-unsubstituted lactams. 

The anionic process is the only method allowing the ROP of the stable five- and six-membered lactam rings, 2-pyrrolidone and 2-piperidone. Obviously, as already mentioned, only N-unsubstituted lactams can be polymerized by the anionic... 

Out of the five to thirteen rings of unsubstituted lactams that can imdergo polymerization, the only laaams, besides CL, intensively studied in terms of anionic ROP are 2-pytrofidone and (o-laiuolactam. Also 2-piperidone deserves some considerations in this respect, although it has been much less studied than the other two lactams. 

Of the various imines known to condense with active methylene compounds, a-arylimines have been the most widely used, especially in earlier work, because of their stability, ease of preparation and the absence of enolizable protons. Aliphatic imines containing enolizable protons have broader synthetic applications but their use is more restricted because they are prone to deprotonation and self aldol type condensations. As will be discussed, new methods utilizing Lewis acids and the less basic boron enolates have been devised to overcome the problem of deprotonation. Other innovations that have extended the scope of imine condensations include in situ methods for the preparation of elusive formaldehyde imines (CH2=NR2) and the utilization of /V-heterosubstituted imines (N = Si, O and S) for the synthesis of primary Mannich bases and /V-unsubstituted -lactams, available via hydrolysis or reduction of the N— bond. 

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