Enamines arylation

In the reactions of benzyne with enamines, arylated enamines or amino-benzocyclobutenes can be obtained, depending on reaction conditions and the structure of the enamine. Thus the presence of a proton source such as a secondary amine will favor the enamine product through capture of the zwitterionic intermediate, whereas in the absence of protons one sees... 

The arylation of morpholinocyclohexene with 2- or 4-chloroquinoline N-oxide or 4-chloropyridine N-oxide and benzoyl chloride led to cyclohexanone a-substituted with the respective chloroquinolines or 4-chloropyridine (691). 2,4-Dinitrofluorobenzene reacted with 2-benzylidene-3-methylbenzothiazoline to give the enamine arylation product (672). 

Synthesis of 1,2-disubstituted indole frameworks 257 via a formal 4 - - 1 cydoaddition between a 4-carbon unit and a primary amine was recently developed by Ackermann (Scheme 9.90) [242]. Reactive intermediates, 2-(o-haloaryl)enam-ines 256 were generated via the Cu(I)-catalyzed hydroamination of the orfHo-halo-substituted phenylacetylenes 254 with primary amines 255. A subsequent Cu(I)-catalyzed intramolecular enamine arylation reaction gave the corresponding indoles 257 in good yields. The authors demonstrated that alkynyl chlorides 254 could also participate in this cascade double amination process, albeit with a substantially diminished efHdency. 

Allylic amines are coupled to halides giving either allylic amines or enamines depending on the reaction condition. Reaction of steroidal dienyl triflate with Boc-diprotected allylamine affords allylamine. Use of AcOK as a base is crucial for the clean coupling[102]. The tert-allylic amine 123 reacts with an aryl halide to give the enamine 125 in DMF and allylic amine 124 in nonpolar solvents[103]. 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Aryl halides with a halogen activated by electron-withdrawing groups react with pyrrolidine enamines of cyclic ketones (68) to give the a-arylated ketones after hydrolysis. The enamine (28) with 2,4-dinitrochlorobenzene gave an excellent yield of 2(2,4-dinitrophenyl)cyclohexanone (88). The... 

The enamine (28) did not undergo C arylation with p-nitrochlorobenzene under these conditions, and at higher temperatures N arylation and subsequent eleavage with formation of N-(4-nitrophenyl) pyrrolidine takes place (68). 

Low yields of C-arylated ketones have also been obtained by reaction of pyrrolidine enamines with diaryl iodonium salts (68). 

Arylation of enamines with p-benzoquinones takes a somewhat different course (70). The enamine (16) reacts exothermally with p-benzoquinone in benzene solution to give 2-(dimethylamino)-2,3-dihydro-3,3-dimethyl-5-benzofuranol (92). The reaction of enamines with quinone dibenzenesul-fonimide proceeds similarly (68). The product from the enamine (28) is the tetrahydrocarbazole derivative (93). 

The reaction of an alicyclic enamine with benzyne intermediate yields simple arylation products and/or 1,2-cycloaddition products, depending upon the reaction conditions 102). This is illustrated by the reaction of l-(N-pyrrolidino)cyclohexene with benzyne (86) (obtained from fluoro-benzene and butyl lithium or o-bromofluorobenzene and lithium amalgam), which produces benzocyclobutene 87 102). 

The photocyclization of N-aryl enamines derived from cyclic or acyclic ketones proceeds under mild conditions to produce 2,3-dihydroindole derivatives (178b). The stereochemistry of the products is predominantly trans, which follows from a photochemical electrocyclic process which should take place in a conrotatory manner (178c,I78d). However, the presence of some cis products is not as easily explained. 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

The reactions of enamines with positively activated olefins have been extended to arylations with />-quinones (350,362-369) and quinone sulfoni-mides (365-368,370). Thus a new pathway for the facile formation of benzofurans and indoles became available. 

In the arylations of enamines with very reactive aryl halides (352,370) such as 2,4-dinitrochlorobenzene, the closely related mechanistic pathway of addition of the enamine to the aromatic system, followed by elimination of halide ion, can be assumed. The use of n-nitroarylhalides furnishes compounds which can be converted to indolic products by reductive cycliza-tion. Less reactive aryl halides, such as p-nitrochlorobenzene, lead only to N-arylation or oxidation products of the enamines under more vigorous conditions. 

Diaryliodonium salts also reacted with enamines to give a-aryl ketones in low yields (370). 

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

Phenylmercury derivatives of 3-aminomethylene-l-methyloxindols have also been investigated (79KGS65). For studies of the effect of substituents on the electronic structure of silver and potassium salts of 3-(aryl)imi-nooxindole see 76MI2. The keto-enol and imino-enamine tautomerism of compounds of type 127 (with 128 and 129) has been investigated (85KGS921). 

The Willgerodt reaction starts with the formation of an enamine 4 from the ketone, e.g. from acetophenone 3. The further course of the reaction cannot be described by a single mechanism that would apply to all examples known. For aryl methyl ketones 3 the mechanism for the Kindler variant is formulated as follows ... 

The disclosure, in 1982, that cationic, enantiopure BINAP-Rh(i) complexes can induce highly enantioselective isomerizations of allylic amines in THF or acetone, at or below room temperature, to afford optically active enamines in >95 % yield and >95 % ee, thus constituted a major breakthrough.67-68 This important discovery emerged from an impressive collaborative effort between chemists representing Osaka University, the Takasago Corporation, the Institute for Molecular Science at Okazaki, Japan, and Nagoya University. BINAP, 2,2 -bis(diphenylphosphino)-l,l -binaphthyl (Scheme 7), is a fully arylated, chiral diphosphine which was introduced in... 

The second method is based on the optically active enamine formed from (S)-prolinol methyl ether and cyclohexanone. This enamine reacts spontaneously with 2-(arylmethylcnc)propane-dioates to give, after hydrolysis, the 2- (.S )-aryl[(,S )-2-oxocyclohexyllmethyl propanedioates 4 in 35-76% yield with d.r. 94 6 > 97 361. 

The Michael additions of chiral cycloalkanone imines or enamines, derived from (FV l-l-phcnyl-ethanamine or (5)-2-(methoxymethyl)pyrrolidine, are highly diastereofacially selective reactions providing excellent routes to 2-substituted cycloalkanones. This is illustrated by the addition of the enamine of (S)-2-(methoxymethyl)pyrrolidine and cyclohexanone to 2-(aryl-methylene)-l,3-propanedioates to give, after hydrolysis, the (2 5,a.S )-oxodicstcrs in 35-76% yield with d.r. (2 S,aS)/(2 S,a/ ) 94 6- > 97 3 and 80-95% ee214. 

In a related study, the reaction of the enamine, l,2-dihydro-3-(2-methoxymethyl-l-pyrrolidin-yl)naphthalene [from 3,4-dihydro-2(l//)-naphthalenonc and (S)-2-(methoxymethyl)pyrrolidine] with 2-aryl-l-nitroethenes gave, after hydrolysis, an 83 17 to 95 5 mixture of the (3S,YR)- and (1/ ,1 T )-nitro ketones31. 

The TS proposed for these proline-catalyzed reactions is very similar to that for the proline-catalyzed aldol addition (see p. 132). In the case of imines, however, the aldehyde substituent is directed toward the enamine double bond because of the dominant steric effect of the (V-aryl substituent. This leads to formation of syn isomers, whereas the aldol reaction leads to anti isomers. This is the TS found to be the most stable by B3LYP/6-31G computations.199 The proton transfer is essentially complete at the TS. As with the aldol addition TS, the enamine is oriented anti to the proline carboxy group in the most stable TS. 

---