N-alkyl maleimides

Engberts [3e, 9] has extensively investigated the Diels Alder reaction in aqueous medium. Recently Engberts and colleagues reported [9c] a kinetic study of a Diels Alder reaction of N-alkyl maleimides with cyclopentadiene, 2,3-dimethyl-1,3-butadiene and 1,3-cyclohexadiene in different solvents. The reaction rates of the cycloadditions with the open-chain diene relative to w-hexane are reported in Table 6.3. The aqueous medium greatly accelerates the Diels Alder reaction and the acceleration increases as the hydrophobic character of the alkyl group of the dienophile increases. These and other kinetic data [3e, 9], along with the observation that the intramolecular Diels-Alder reaction is also accelerated in... 

Chiral pyrrolo[d]thiepine 166 can be obtained efficiently in 63% yield starting from N-alkylated maleimide 164. Successive Michael addition of phenethyl thiol and regioselective reduction are followed by spontaneous loss of hydrogen by N-acyliminium intermediates 165 and 7r-aromatic intermolecular a-amidoalkylation... 

N-Alkyl maleimides. A short route to these compounds involves reaction of maleic anhydride (1) with amines to form malcamic acids (2, >95% yield). On treatment of these products with oxalyl chloride, the hydrochlorides 3 arc obtained. Elimination of HC1 affords the desired maleimides (4), which are obtained in 55-73% overall yield. 

Addition of the thiol across the ene double bond is exothermic, with reaction enthalpies ranging from -10.5 kcal mol" for the electron-rich vinyl ether donble bond to -22.6 kcal mol" for the electron-poor double bond of, for example, a N-alkyl maleimide [4]. 

Stable triazolines are obtained from aryl azides and V-alkyl and N-aryl maleimides (Scheme 81 )307-309a the reaction succeeds with silyl azides310 and is utilized in the synthesis of polymers from bisazides and bismaleimides.311 312 Unlike maleimides, maleic anhydrides do not yield stable triazolines with trimethylsilyl azide the reaction products are oxazinediones (Section IV,A).310,313,314... 

In 1983 Bryant and Coyle described the cyclization of N-(co-morpholino-alkyl)-maleimides 107, which is initiated by a photo-induced electron transfer (Sch. 35) [77]. To the best of our knowledge,... 

Azo compounds like esters or imides of azo dicarboxylic acid act as reactive dienophiles in normal electron demand hetero Diels-Alder reactions due to the strong activation caused by two electron-withdrawing moieties. In the last years, considerable attention has focused on alkyl and phenyl derivatives of 1,2,4-tria-zoline-3,5-diones since their cycloadditions to chiral dienes proceed with often excellent facial selectivities. Thus, when reacting an oxapropellane derived diene with N -methyltriazolinedione, Paquette et al. obtained the cycloadduct as single diastereomer, but both maleic anhydride and N-phenyl maleimide were distinctly less reactive and turned out to undergo cycloadditions with poor selectivities [289]. 

N-Alkyl or N-aryl succinimides can be prepared from the corresponding amines (107) or from succinic anhydride, ammonia, and the corresponding alcohol (108). Succinimides are also obtained by vapor-phase hydrogenation of the corresponding maleimides in the presence of a catalyst (109). 

Hoveyda et al. [262] prepared different N-aryhnaleimidobenzoic acids linked to SASRIN resin, whose double bond present in the maleimido moiety could act as a convenient dipolarophile in cycloaddition reactions. Thus, solution-generated a-iminoesters (from different aromatic aldehydes and aminoesters) were reacted vdth the supported maleimides (158) under Tsuge [263] conditions. Formation of the expected syn-endo cycloadduct (160) was observed after only 1 h at room temperature (Scheme 33). From structure-reactivity analysis, the authors concluded that the cycloaddition reaction is more sensitive to steric then to electronic factors on the azomethine yhde counterpart. The advantage of this procedure stems essentially from the fact that the iminoesters (159) are formed in situ. Aldehydes containing a-hydrogens could also be employed. Moreover, the resin in this case also plays the role of a protective group, because, in contrast with N-alkyl and N-aryl (see above) maleimides, N-unsubstituted maleimide is not suitable for 1,3 dipolar cycloadditions. 

The cycloadducts from Af-phenylmaleimide and anthranil have been reformulated.219 The lower melting (mp 190°C) isomer is the exo rather than the endo adduct, whereas the supposed exo adduct (mp 231°C) is in fact (o-formylanilino)-lV-phenylmaleimide. Cycloadducts have also been obtained with maleimide and its N-alkyl derivatives.220... 

Reaction of W-acyl-2-phenyl-l. 2-dihydropyridines with maleimides proceeds with endo-maleimlde anf/-phenyl stereochemistry,351 contrary to an earlier report. Pyrroles lacking electron-withdrawing substituents at N fail to give [4+2J adducts with DMAD even at high pressure 36 5-pivaloyl-2H-isoindole is a stable crystalline material which nevertheless readily forms Diels-Alder adducts with N-alkyl and W-aryl maleimides.37 The 1 3 adduct (27) is among the products from reaction of DMAD with 3-ethoxy- 1-methylisoindole.36... 

N-substituted maleimides are known to be alkylating agents that react with thiols to form stable thioethers, at neutral pH (Scheme 6.16). Hydrolysis can also occur but its rate depends on the nature of the substituent [106]. 

Scheme 6.16 Hydrolysis and alkylation and of N-substituted maleimides by thiols.

Synthesis of monomers N-[n-(4 -cyanobiphenyl-4-yloxy)alkyl]maleimides (Mb) were prepared via the Mitsunobu reaction previously described for the condensation of alcohols with maleimide (yield 90-95%) and subsequent deprotection of the maleimide double bond by a retro-Diels-Alder reaction (yield 80-95%) as outlined in Scheme 1. 

Synthesis of polymers Poly N-[n-(4 -cyanobiphenyl-4-yloxy) alkyl] maleimide s (PMb) and poly[p-(4 -cyanobiphenyl-4-yloxy) methylstyrene-co- N-[3-(4 -cyanobiphenyl-4-yloxy)propyl] maleimide ] [PfCBMS-co-Ma)] were obtained by free radical polymerization (AIBN, 2 mol%) in DMSO ([monomer]=0.6 mol/L) under vacuum in sealed tubes at 70" C for 48 h. 

The formation of the carbon sulfur bond follows an anti-Markovnikov regios-electivity, which ensures the formation of the most stable carbon radical [42]. There are several reports establishing a general trend for the reaction of thiols with alkenes. Comprehensive reports in this regard were published by Hoyle et al. [43], where they compared the reaction of three families of thiols, namely alkyl-3-mercaptopropionates, alkyl thioglycolates, and alkyl thiols, with various alkenes. The reactivity order provided by them is as follows norbornene > vinyl ethers > propenyl > alkenes allyltriazines allyl isocyanurates > acrylates > N-substituted maleimides > acrylonitrile methacrylates > styrene > conjugated dienes. 

Vinylpyridines add to TV-alkyl- or phenyl-substituted maleimides to give unexpected 1 2 and 1 3 adducts. From the reaction of 2-vinylpyridine 99 with N-alkylmaleimides the 1 2 addition products 154, which are tetra-hydroquinoline derivatives, could be isolated in the presence of polymerization inhibitors. Furthermore, 1 3 adducts 155 are formed, representing an unusual type of cycloaddition involving the pyridine ring. On the other hand, 4-vinylpyridine 156 combines with 3 moles of dienophilic N-alkylmaleimides in the presence of polymerization inhibitors to afford the spiro compounds 157 (73HCA440). 

The efficiency of photoaddition of maleimides to benzene strongly depends on the N-substituent [37,75], Substituents possessing a ir-clectron system that can have significant overlap with the nitrogen lone-pair orbital (phenyl, m- and p-tolyl, p-methoxyphenyl) almost completely inhibit the reaction. Maleimides with substituents which either have no -rr-electron system (H, alkyl) or have a ir-electron system which is prevented from significant overlap with the orbital on nitrogen (benzyl, o-tolyl, 2,6-xylyl) show efficient reaction. The lack of reactivity of maleimides with conjugating substituents is considered to result from the... 

The photolysis of Barton esters (N-hydroxy-2-thiopyridone esters, 43) proved to be an efficient method for generating carbon-centered radicals that are exploited for the regioselective alkylation of electron-deficient olefins a thiopyridyl unit is likewise incorporated into the end products. In a recent application, Barton esters were found useful in the synthesis of natural and unnatural disubstituted maleimides or maleic anhydrides by way of two consecutive radical addition steps, as described in Scheme 3.27 [72]. 

Further examples for electron acceptor monomers are acrylonitrile [37], diethyl fumarate [39], fumaronitrile [29,30, 38], maleonitrile [38], N-carbethoxymaleimide [29], N,N-diethylaminoethyl methacrylate [39], nitroethylene [10] and iV-ethyl-maleimide [40], As electron donor monomem also are used vinyl alkyl ethers [38, 40], alkyl methacrylate [40], JV-vinyl pyrrolidone [40] and cyclohexene oxide [10]. 

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