Imine, Cyclopropyl

Finally a general approach to synthesize A -pyrrolines must be mentioned. This is tl acid-catalyzed (NH4CI or catalytic amounts of HBr) and thermally (150°C) induced tea rangement of cyclopropyl imines. These educts may be obtained from commercial cyan> acetate, cyclopropyl cyanide, or benzyl cyanide derivatives by the routes outlined below. Tl rearrangement is reminiscent of the rearrangement of 1-silyloxy-l-vinylcyclopropancs (p. 7 83) but since it is acid-catalyzed it occurs at much lower temperatures. A -Pyrrolines constitut reactive enamines and may be used in further addition reactions such as the Robinson anei lation with methyl vinyl ketone (R.V. Stevens, 1967, 1968, 1971). 

Cyclopropyl ketones 32 and cyclopropyl imines 33 can also undergo [3+2] cycloaddition reactions with enones 34 in presence of NHC-Ni complexes to afford the corresponding cyclopentane compounds 35 (Scheme 5.9) [11]. The catalytic system is prepared in situ from the use of [Ni(COD),], SIPr HCl salt and KOBu, the reaction also required the use of Ti(O Bu) as an additive to improve yields and increase reactions rates. In most of the cases, th products 35 were obtained in good to excellent diastereoselectivities. 

Scheme 5.9 NHC-Ni catalysed [3-I-2] cycloaddition reaction of cyclopropyl ketones or cyclopropyl imines with enones...

Cyclopropyl imines can be used as five-atom components in intermolecular [5 + 2]-cycloaddition reactions with dimethylacetylene dicarboxylate (DMAD) (Scheme 14).45 In this hetero-[5 + 2]-cycloaddition reaction, dihydroaze-pines are constructed from simple, readily available starting materials. The cyclopropyl imines can be preformed or made in situ by the condensation of cyclopropyl carboxaldehydes and amines. Although, thus far, DMAD is the only... 

In order to gain a more complete picture of the photoreactivity of azadiene 68, this compound was irradiated using DCA as a SET sensitizer. Surprisingly, under these conditions, two products are formed that were identified as the vinyla-ziridine 70 (11%) and the cyclopropyl imine 88 (19%) as shown in Scheme 13 [63],... 

An impressive number of alkaloids has been generated from the synthon (202), which is accessible by an acid catalyzed rearrangement of the appropriately substituted cyclopropyl-imine. The endocyclic enamine (202) should react with electrophiles on the /8-carbon in a process which simultaneously renders the a-carbon electrophilic and therefore susceptible to capture by nucleophilic reagents. The application of this methodology to the synthesis of ipalbidine (191a) and septicine (204) is shown in Scheme 30. Here, the unusual 3-phenylthio-2-pyrroline intermediate (203) serves as a relatively stable equivalent synthon of the unsubstituted 2-pyrroline analogue which is notoriously unstable (77ACR193). 

Substituted 4,5-dihydroazepines 321 (e.g., R1 = Bn, R2 = R3 = H, R4 = M e 82% yield) may be prepared in high yield by a rhodium-mediated hetero-[5+2]-cycloaddition of the cyclopropyl imines derived from 318 on reaction with the primary amines 319, with dimethyl acetylenedicarboxylate 320 (Equation 48) <2002JA15154>. 

If there are heteroatoms in the molecule, the [1,3] shift can be catalysed by acids or Lewis acids. The heterocycle 49, needed for a synthesis of alkaloids from narcissi, is formed from the cyclopropyl imine 48 with HBr catalysis.12 The imine 48 comes from an aldehyde 47 made in the same way as 43. 

The dicyclopropyl ketimine 198 prepared from the 0,N-cyclopropanone hemiacetal 194 (vide supra, Sect. 4.9, Eq. (62)), heated in xylene with ammonium chloride for 4 hr underwent ring expansion exclusively to the enamine 399 followed by isomerization to the cyclopropyl pyrroline 400. Although further ring expansion was not observed on prolonged heating, 400 was converted to the hydrobromide 401 with anhydrous HBr 2091 which upon heating to 140 °C for 10 min experienced a second cyclopropyl imine rearrangement to provide the pyrrolizidone 403 in 51 % yield, most probably via the HBr adduct 401 by cyclization to the pyrroline 402 followed by acid-induced hydrolysis, Eq. (95) 129). 

Wender et al. reported that the rhodium-catalyzed hetero-[5 + 2]-cycloaddition of the cyclopropyl imines 446 and dimethyl acetylenedicarboxylate gave the dihydroazepines 447 in high yields (Scheme 141).202 The rhodaheterocycle intermediate 448 is formed upon treatment of 446 with the rhodium catalyst, which undergoes insertion of the alkyne to give 449, and finally the reductive elimination of Rh gives 447. 

Kamatani et al. reported that Ru3(CO)i2-catalyzed carbonylative [5 + 1]-cycloaddition of the cyclopropyl imines 500 gave the six-membered unsaturated lactams 501 (Scheme 151).213 The reaction proceeds through the formation of ruthenacycle 502. 

Recently, Curran and Liu [63] encountered an interesting 1-exo dig cyclization reaction during their attempts to use cyclopropanes as radicophiles. Reaction of the bromodinitrile 255 with an excess of BusSnH and AIBN resulted in the formation of the eight-membered enaminonitrile 257, whose formation was explained by initial 1-exo dig cyclization of the radical onto one of the nitriles followed by BusSnH-mediated cleavage of the cyclopropyl imine 256. 

An interesting synthesis of ( )-[2 - C]nicotine using the cyclopropyl-imine synthon (for other applications, see Vol. 2, p. 133 and Vol. 3, p. 211) has been reported. Thus treatment of 3-[ C]-cyanopyridine with cyclopropyl-lithium gave, after hydrolysis, the ketone (29) which, when refluxed in N-methylform-amide, produced (+)-[2 - C]nicotine. 

The scope of catalytic ring-opening [3+2] cycloadditions was expanded to include simple cyclopropyl ketones, which combine with vinyl ketones to provide substituted cyclopentane derivatives (Scheme 3-32). Cyclopropyl imines were also found to be effective cycloaddition substrates under similar conditions, as illustrated in the sample procedure below. " Oxidative additions of nickel(O) to cyclopropyl ketones were found to produce six-membered metallacyclic nickel (9-enolates, which were competent species in the [3+2] cycloaddition process. " ... 

In 2000, a selective cycloaddition of cyclopropyl imines, derived from cyclopropyl phenyl ketone and tert-butylamine and CO (2 bar), was developed by the same group (Scheme 1.5) [16]. The reaction was allowed to proceed in toluene (3 ml) in presence of a catalytic amount of Ru3(CO)j2 (0.02 mmol) at 160°C for 60 h, giving the pyridinone derivative in 76% isolated yield. 

Scheme 1.5 Ruthenium-catalyzed carbonylative reaction of cyclopropyl imines.

The rearrangement is analogous to the di-n-methane rearrangement and is considered as 1,2-shift of imino group from C(3) to C(4), followed by a o bond formation between C(3) and C(5). For example, the photorearrangement of P,y-unsaturated imine 55 gives cyclopropyl imine 56, which on hydrolysis gives cyclopropane aldehyde 57 [62]. 

An interesting solution to the synthesis of the alkaloids ( )-isoretronecanol (44) and ( )-trachelanthamidine (45) is provided by the thermal rearrangement of cyclopropyl imines " as shown in Scheme 75. Alternative syntheses of (-i-)-isoretronecanol and of the related alkaloids (+)-laburnine and (+)-supindine have also been reported.An important reaction used was the regiospecific... 

Cyclopropyl imines 95 undergo a ruthenium catalyzed [5-1-1] cycloaddition reaction with CO to give the unsaturated lactames 96 in good yields . ... 

In contrast to cyclopropyl ketones that function as three-carbon annulation units, cyclopropyl imines can participate in annulation as five-atom units. Carbonylative [5+1] annulation of cyclopropyl imine 126 was catalyzed by metal carbonyl complexes to afford six-membered unsaturated lactam 127 (Scheme 2.84) [62,138]. 

Dihydroazepine 128 were obtained from [5+2] annulation of cyclopropyl imine 129 and alkyne 130 catalyzed by a rhodium(I) complex (Scheme 2.85) [139]. 

Ruthenium-catalyzed carbonylative [5+1] cyclo-addition of cyclopropyl imines and CO Summary References... 

Ruthenium-Catalyzed Carbonylative [5+1] Cycloaddition of Cyclopropyl Imines and CO... 

CO workers [23]. From cyclopropyl imines instead of cyclopropyl olefins, the corresponding six-membered unsaturated lactams were produced. The substituent on the imine nitrogen was pivotal to the reaction. To get products in good yields, the A-substituent can be tert-butyl or cyclohexyl but not butyl, benzyl, para-methoxyphenyl, or methoxy group (Scheme 17.28). 

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