Tetrahydropyridines => dienes

Azadienes undergo Diels-Alder reactions to form pyridine, dihydro- and tetrahydropyridine derivatives. N-Vinyl lactim ethers undergo Diels-Alder reactions with a limited set of dienophiles. " Thioketones react with dienes to give Diels-Alder cycloadducts. The carbonyl group of lactams have also been shown to be a dienophile. Certain heterocyclic aromatic rings (among them furans) can also behave as dienes in the Diels-Alder reaction. Some hetero dienes that give the reaction are -C=C-C=0, 0=C-C=0, and N=C-C=N. ... 

Some cases are known in which Diels-Alder reactions of electron-deficient allenes and dienes compete with [2 + 2]-cycloadditions (see also Section 7.3.7) [12, 151, 335, 336]. Recently, a phosphane-catalyzed [4 + 2]-annulation starting from allenic ester 337 and N-tosylaldimines 338 was published [337]. However, the formation of the tetrahydropyridines 339 isolated in excellent yields is explained by a multi-step mechanism and only resembles a Diels-Alder reaction. 

The cycloaddition of dienes to imines to form tetrahydropyridines (equation 46) has been investigated extensively40. Ordinary imines are not sufficiently reactive to add to dienes they have to be activated by the presence of electron-withdrawing substituents. Thus the triester 70 adds to cyclopentadiene under atmospheric pressure to form 71 (equation 47). The reactions with other dienes (cyclohexadiene, isoprene or 2,3-dimethylbuta-l,3-diene) require high pressures41. 

Oximes of type XON=CW2 (X = Ts, Tf, Ac W = CN, COiEt) are of interest as cycloaddition partners in [4-1-2] cycloaddition reactions of dienes For example, addition of acetoxyimino Meldrum s acid to dienes at high pressure afforded tetrahy-dropyridine derivatives. Recently, such reactions were studied in detail by Renslo and Danheiser. Thus, Diels-Alder cycloaddition of oximinotosylate 292 with a variety of 1,3-dienes afforded tetrahydropyridines 293, which can be easily transformed to... 

Intramolecular [4 + 2] cycloaddition reactions of enamides have provided a route to hydroindole and hydroquinoline ring systems (80JA3294,5274). In this work, the diene portion was initially masked as a 2-substituted 2,5-dihydrothiophene 1,1-dioxide. Thus, reaction of the acid chloride (312) with 3,4,5,6-tetrahydropyridine (311) afforded the masked enamido diene (313), which was converted to the enamido diene (314) upon brief refluxing in xylene. Thermolysis of (314) afforded the hydrolulolidine (315) in 45-55% yield. Additionally, (313) could be transformed to (315) directly by passage of a 1% solution in toluene through a vertical tube (600 °C oven temperature) (Scheme 67). The method was used to prepare a known precursor to aspidospermine. 

The preparation of conjugated dienes from pyridines is exemplified by the transformation of 2-picoline into the sex pheromone (669) of Lobesia botrana, a major pest of vineyards (Scheme 154) (80TL67). Thus, the lithio salt of 2-picoline was alkylated by 2-(5-chloropentyl-oxy)tetrahydropyran, the resulting pyridine (665) N-methylated, and the pyridinium salt reduced by sodium borohydride. Quaternization of the 1,2,3,6-tetrahydropyridine (666) and Hofmann elimination gave the (7 , 9Z)-undecadien-l-ol (667) as the sole isomer. Protection of the alcohol and treatment of the corresponding ammonium salt (668) of the amine with lithium dimethylcuprate gave pure (669) after hydrolysis, acetylation and HPLC purification. 

Diels-Alder reactions of a,fi-unsaturatedN,N-dimethylhydrazones.1 These readily available hydrazones can function as 1-amino-l-aza-l,3-dienes in Diels-Alder reactions. Thus, 1 undergoes regioselective cycloaddition with various electrophilic dienophiles to give tetrahydropyridines such as 2 and 3. Unfortunately, removal of the dimethylamino group with zinc and acetic acid (or other reagents) also effects reduction of the double bond. The initial adduct from cycloaddition of 1 with naphthoquinone is unstable and undergoes spontaneous elimination of the elements of dimethylamine to give the aromatic adduct 4. 

The 4 + 2-cycloaddition of 2-substituted 1,2-dihydropyridines with nitrosoben-zene produces [2.2.2]bicycloadducts, which are readily reduced by alane to trans-2-substituted 3-amino-l,2,3,6-tetrahydropyridines stereospeciflcally.123 The intramolec- (g) ular nitroso-Diels-Alder reaction of a-acetoxynitroso derivatives in aqueous medium produces 3,6-dihydro-l,2-oxazines in high yield.124 The nitroso-Diels-Alder reaction of acyclic OTIPS-dienes (115) and 6-methyl-2-nitrosopyridine (114) in the presence of (g) [Cu(MeCN)4(difluorosegphos)]PF6 yielded the dihydro 1,2-oxazine cycloadduct (116) with high yield and enantioselectivity (Scheme 33). 125 (Fe)... 

The formation of tetrahydropyridines by reaction of a suitable diene with an imino dienophile is a reaction known since more than half a century [177] and has been intensively studied. In general, the imines react as the electron-deficient component and their reactivity strongly depends on the electron density which may be tuned by activating or deactivating moieties. However, exceptions from this rule are possible as found by Padwa et al. [178]. They described cycloadditions of imines to bis(phenylsulfonyl)-1,3-butadienes. 

RCM reactions are most frequently employed in the synthesis of 2,5-dihydrofurans as well as dihydropyrrole derivatives . Likewise, RCM provides the most general approach to 3,6-dihydropyrans . In a specific example, dihydropyran 127 bearing a chiral oxacyclic diene can be constructed via enyne metathesis of the chiral ether 126 (Scheme 68) <2002T5627>. The analogous tetrahydropyridine derivatives are prepared by a similar RCM procedure . 

Fry, in a search for an intermediate capable of undergoing stereospecific cyclization to 11/3-alkylbenzomorphans, studied the 2,3-cis and trans isomers of 2-benzyl-l,3,4-trimethyl-l,2,3,6-tetrahydropyridine (Scheme 4.11). These were prepared from the iminium dienes (80 and 81) isolated as crystalline perchlorates from benzyl Grignard attack on 1,3,4-trimethylpyridinium bromide. The isomeric dienes were differentiated through their cyano derivatives (82 and 83), which on borohydride reduction gave the isomeric tetrahy-dropyridines, 84 and 85. Elimination of HCN from 82 gave the iminium diene (86) isomeric with 81. Addition of nitrile to 81 followed by borohydride reduction resulted in the appropriate trans tetrahydropyridine (88) that cyclized to the 11/3-methylbenzomorphan (89). 

In the presence of 10 mol % Sc(OTf)3, A-benzylideneaniline reacts with 2-trans-l-methoxy-3-trimethylsiloxy-l, 3-butadiene (Danishefsky s diene) [23] to afford the corresponding aza Diels-Alder adduct, a tetrahydropyridine derivative, quantitatively (Eq. 7) [24]. In the reaction of A -benzylideneaniline with cyclopentadiene under the same conditions, on the other hand, the reaction course ehanged and a tetrahydroqui-noline derivative was obtained (Eq. 8). In this reaction, the imine aeted as an azadiene toward one of the double bonds of cyclopentadiene as a dienophile [25]. In the reaction with 2,3-dimethylbutadiene a mixture of tetrahydropyridine and tetrahydroqui-noline derivatives was obtained. A vinyl sulfide, a vinyl ether, and a silyl enol ether worked well as dienophiles to afford the tetrahydroquinoline derivatives in high yields [26,27]. 

Sc(OTf)3-catalyzed three-component coupling reactions of aldehydes, amines, and dienes have been examined. In the presence of 10 mol % Sc(OTf)3 and magnesium sulfate, benzaldehyde was treated with aniline and Danishefsky s diene. The desired three-component reaction proceeded smoothly to afford the corresponding tetrahydropyridine derivative in 83 % yield (Eq. 9) [24b]. Under the same reaetion conditions, cyclopentadiene was used instead of Danishefsky s diene to afford the corresponding tetrahydroquinoline derivative (Eq. 10). Different combinations of aldehydes, amines, and alkenes are possible in these reactions, and afford diverse tetrahydroquinoline derivatives in high yields. 

At a loading as low as 0.5 mol%, indium triflate catalyzes the three-component coupling reaction between aldehydes, amines, and Danishefsky s diene to afford tetrahydropyridine derivatives (Scheme 8.106) [138]. In fhe presence of indium triflate, 3,4-dihydro-2H-pyran reacts with in sitw-generated chromone Schiff s bases to give the endo cycloadducts (Scheme 8.107) [139]. 

As a rule, cycloadditions with acyclic N-acyl imino dienophiles are useful synthetic reactions which demonstrate excellent regio- and stereo-selectivity. A commonly used source of N-acyl immonium dienophiles are bis-urethanes such as (13) (equation 5), which upon treatment with a Lewis acid and a diene afford Diels-Alder adducts. In this case, (13) reacts with boron trifluoride etherate to afford immonium ion (14) which adds to diene (15), yielding tetrahydropyridine (16). ... 

The Diels-Alder cycloaddition of a dehydrohydantoin has been utilized as a key step in a total synthesis of the antitumor antibiotic streptonigrin (33) (equation 10). Addition of diene (30) to hydantoin (24) afforded a 1 3 mixture of the tetrahydropyridines (31) and (32). The desired regioisomer (32) was converted in several steps to the natural product. 

An interesting series of 2-trifluoromethyl-tetrahydropyridines was prepared by RCM of diene precursors, exemplified by the conversion of 216 to 217 in 98% yield with 98% de <05EJO1258> (Scheme 62). 

Cross-conjugated enamines like 2-morpholinobutadienes (319) react with benzylide-neaniline (320) in the presence of ZnClj to give tetrahydropyridine (322) with a high degree of stereoselectivity . The high stereoselectivity was explained by assuming that the reaction takes place in a concerted manner via coordination of diene and dienophile to the Lewis acid (equation 69). 

In the presence of 10 mol% of ytterbium triflate (Yb(OTf)3> a representative lanthanide triflate), N-benzylideneaniline (10a) was treated with 2-trimethylsi-loxy-4-methoxy-1,3-butadiene (Danishefsky s diene, 11) [59] in acetonitrile at room temperature. The imino Diels-Alder reaction proceeded smoothly to afford the corresponding tetrahydropyridine derivative in a 93% yield (Table 19). The adduct was obtained quantitatively when Sc(OTf)3 was used as a catalyst. Imines 10b and 10c also reacted smoothly with 11 to give the corresponding adducts in high yields. The reaction of 10a with cyclopentadiene was performed under the same reaction conditions. It was found that the reaction course changed in this case and that a tetrahydroquinoline derivative was obtained in a 69% yield. In this reaction, the imine worked as an azadiene toward one of the double bonds of cyclopentadiene as a dienophile [43,60]. In the reactions of 2,3-dimethylbutadiene, mixtures of tetrahydropyridine and tetrahydroquinoline derivatives were obtained. 

Imines with acceptor substitutents, for instance the A/ -tosylimine of the glyoxylic ester 187, add to 1,3-dienes (e.g. 2,3-dimethylbuta-1,3-diene) to produce tetrahydropyridines (e.g. 188). Elimination of sulfinic acid, saponification and dehydrogenation lead to pyridine-2-carboxylic acids (e.g. 189) ... 

Treatment of 1-methyl-1,2,3,6-tetrahydropyridine (105) with base gives l-methyl-l,2,3,4-tetrahydropyridine (106). The enamine (106) is estimated to be at least 4.0 kcal mol more stable than the allylamine (105) (Scheme 41). Irradiation of (105) with light of wavelength 185 nm results in the formation of buta-1,3-diene and the cyclic trimer (107). At 10% conversion, the yields of butadiene and H2C=NMe monomer are 74 and 22% respectively. 

---