Cycloaddition reactions sealed tube

Since the first demonstration of a cycloaddition reaction of a, /f-unsaturated sulfones in 1938 by Alder and coworkers85, a variety of a, /3-unsaturated sulfones have been prepared and used as dienophiles. For example, when a mixture of p-tolyl vinyl sulfone and 2,3-dimethylbutadiene in benzene is heated at 145-150 °C for 10 h in a sealed tube, crystals of the cycloadduct (134) are obtained (equation 102). Other examples of this intermolecular cycloaddition reaction are given in Table 12. 

The intramolecular Diels-Alder reaction of 78 was investigated during the synthesis of isoquinoline alkaloids [65ij. No reaction occurred when solid-phase conditions were used (Florosil in DCM and CaCli) or when a variety of Lewis acids were employed (SnCU, BF3, RAICI2, Ti(z — Pr)4-TiCl4). A 56 % yield of 79 was obtained by carrying out the cycloaddition in toluene in a sealed tube at 200 °C. jS-CD catalysis in water under milder conditions (Equation 4.11) improved the conversion to 84 %. 

For 4-nitrophenyl 2-azadiene 617, vigorous reaction conditions are necessary (110°C, sealed tube, 25h) and give bicyclic product 619. The formation of this compound could be explained by [4+2] cycloaddition reaction leading to 618 followed by dehydrogenation (Scheme 99) <1994T12375, 2003H(61)493>. 

Diels-Alder cycloaddition of 5-bromo-2-pyrone with the electron-rich tert-butyldi-methylsilyl (TBS) enol ether of acetaldehyde, using superheated dichloromethane as solvent, has been investigated by Joullie and coworkers (Scheme 6.90) [188]. While the reaction in a sealed tube at 95 °C required 5 days to reach completion, the anticipated oxabicyclo[2.2.2]octenone core was obtained within 6 h by microwave irradiation at 100 °C. The endo adduct was obtained as the main product. Similar results and selectivities were also obtained with a more elaborate bis-olefin, although the desired product was obtained in diminished yield. Related cydoaddition reactions involving 2-pyrones have been discussed in Section 2.5.3 (see Scheme 2.4) [189]. 

Examples of the use of heterodienophiles under the action of microwave irradiation are not common. Soufiaoui [84] and Garrigues [37] used carbonyl compounds as die-nophiles. The first example employed solvent-free conditions the second is an example of the use of graphite as a susceptor. Cycloaddition of a carbonyl compound provided a 5,6-dihydro-2H-pyran derivative. These types of reaction proceed poorly with aliphatic and aromatic aldehydes and ketones unless highly reactive dienes and/or Lewis acid catalysts are used. Reaction of 2,3-dimethyl-l,3-butadiene (31) with ethyl glyoxylate (112) occurred in 75% yield in 20 min under the action of microwave irradiation. When conventional heating is used it is necessary to heat the mixture at 150 °C for 4 h in a sealed tube to obtain a satisfactory yield (Scheme 9.33). 

Dipolar cycloaddition reaction of trimethylstannylacetylene with nitrile oxides yielded 3-substituted 5-(trimethylstannyl)isoxazoles 221. Similar reactions of (trimethylstannyl)phenylacetylene, l-(trimethylstannyl)-l-hexyne, and bis (trimethylsilyl)acetylene give the corresponding 3,5-disubstituted 4-(trimethyl-stannyl)isoxazoles 222, almost regioselectively (379). The 1,3-dipolar cycloaddition reaction of bis(tributylstannyl)acetylene with acetonitrile oxide, followed by treatment with aqueous ammonia in ethanol in a sealed tube, gives 3-methyl-4-(tributylstannyl)isoxazole 223. The palladium catalyzed cross coupling reaction of... 

Reaction of a-allenyl alcohol 147 with methanesulfonyl chloride and triethylamine in toluene at 190 °C, in a sealed tube, led to the tricyclic dihydropyrrolizin-4-one 149 in 35% yield. This transformation involves a domino mesylation/ intramolecular Diels-Alder cycloaddition via diene 148 (Scheme 29) <2002CC1472>. 

Dienes do not react with carbonyl compounds unless the latter are activated by electron-withdrawing substituents such as carboxyl groups. Cyclohexa-1,3-diene, for example, adds diethyl mesoxalate (1) at 120 °C to form 2 (equation 2)2. Other cycloadditions of this ester with various dienes, which were carried out in a sealed tube at 130-135 °C, are shown in equations 3 and 43. It is noteworthy that no product was isolated from the action of diethyl mesoxalate on cyclopentadiene it was suggested3 that the cycloadduct reverted to its components at the high temperature required for the reaction. 

Novel [4+2] cycloadditions of 1-phenyl-1-benzothiophenium triflate salt 89 with dienophiles (cyclopentadiene and 1,3-diphenylbenzofuran) have been reported <990L257>. Heating 89 and cyclopentadiene in CHjClj gave a single product, endo cycloadduct 90. The stereochemistry of 90 was confirmed by single-crystal X-ray analysis. The cycloaddition of 3-methyl-l-phenyl-benzothiophenium triflate salt with cyclopentadiene proceeded only in low yield and required much more rigorous reaction conditions (CHjCN, sealed tube. A). 

A -Sulfonyl-2,2 -biindoles undergo a formal [4-I-2] cycloaddition with various dienophiles to produce indolocarba-zoles <2004TL4009>. Thus, reaction of 171 with A -benzylmaleimide in chlorobenzene in a sealed tube produces the cycloadduct in moderate yield (Equation 105) as the only observable product (Table 11). It is proposed that the reaction proceeds by an initial Michael addition, followed by a rapid cyclization and loss of the phenylsulfonyl group during the aromatization process. Similar cyclization reactions are observed with A -methylmaleimide, dimethylace-tylene dicarboxylate, and 1,4-naphthoquinone. 

To demonstrate the feasibility of Diels-Alder cycloaddition using y-pyrones as dienophiles,47 50 the reaction of 3-cyanochromone 31 with diene 32 in toluene proceeded at 200 °C in a sealed tube for 72 h to give the desired cycloadduct 33 in 80% yield [Scheme 6] without observing any inverse electron demand [4 + 2] cycloadducts.51 However, the endo exo ratio was only 1.3 1 as determined by ]H NMR with the stereochemistry assigned using nOe experiments. 

The use of isoxazole derivatives in organic synthesis is of great interest, but little has been done on the utilization of such compounds as a part of a diene system in [4 + 2]-cycloadditions. 3-Methyl-5-vinylisoxazole 236 gave cycloaddition reactions in a sealed tube in benzene solution at 120°C for 3 days. With the dienophiles acrolein and methyl acrylate, aromatiza-tion of the isoxazole ring via a 1,3-proton shift occurs readily under the reaction conditions, allowing the direct isolation of compounds 237, which are also detected in the mass spectrum of the raw reaction material. The reactions are regioselective (85H2019). 

The participation of the isoxazole ring in cycloaddition reactions (Section II,D,8) prompted the same authors to test the possibility of achieving intramolecular cycloadditions (87H47). Intramolecular cycloaddition was successful with substrates 331, 332, and 333 in CHC13 in a sealed tube above 150°C the cycloadducts were observed by GC-MS monitoring. After 48 hours at 200°C, the isoxazole 331 showed only a 10% conversion to a mixture of cycloadducts 334. The more activated substrates 332 and... 

The intermolecular [4+2] cycloaddition of cyclopentadiene and iV-acetyl-2-azetine 23 occurs when they are heated in toluene in a sealed tube to give a good yield (83%) of the Diels-Alder adduct 317 (Equation 35). Similar high-yielding addition reactions occur with substituted cyclopentadienes and 1,3-diphenylisobenzofuran to give endo-adducts <1999TL443>. 

The unusual 4/6/4 system has been obtained by an intramolecular [2+2] cycloaddition reaction of 2-azetidi-none-tethered enallenols by thermolysis in toluene solution at 220 °C in a sealed tube (Equation 69) <2006CEJ1539>. 

Reaction of 112b with methyllithium followed by alkylation with methyl iodide gives a germophilic product 194. The [2+4]cycloaddition of 112b with 2-methyl-1,3-pentadiene affords 195 regioselectively. When a hexane solution of 195 is heated at 140 °C in a sealed tube in the presence of excess 2,3-dimethyl-l,3-butadiene, a dimethylbutadiene adduct 196... 

Cycloaddition/cycloreversion processes were also employed to temporarily mask the reactive nitrone functionality <2002J(P1)1494, 2002EJ01941>. For example, nitrone 208 was protected by cycloaddition with styrene. The isoxazolidine ring remained unaffected during all the reaction steps used to introduce a pendant dipolarophile and obtain the derivative 209. By heating in a sealed tube at 190 °C, isoxazolidine 209 underwent cycloreversion restoring the nitrone moiety which was directly trapped by an intramolecular 1,3-dipolar cycloaddition to afford 210 with complete regio- and diastereoselectivity (Scheme 47). 

Recently, lupinine 4 and epi-lupinine 139 were also synthesized by Takayama s group (85H2913) based on an intramolecular imino Diels-Alder reaction (Scheme 20). Thermolysis of acetate 141 in toluene containing sodium hydrogen carbonate in a sealed tube at 200 C for 2 hr gave lactam 143 in 80% yield via desulfonylation and subsequent intramolecular cycloaddition of 142. 

Cycloaddition reaction of 2,3-diphenylcyclopropenone with l,3-diphenyl-2//-cyclopenta[/]-phenanthren-2-one in chlorobenzene at 150°C for 80 hours under argon in a sealed tube produced 9,10,12,13-tetraphenyl-ll//-cyclohepta[/]phenanthren-ll-one in 29% yield. 

Takahashi and co-workers [264] constructed two 48-member p-strand mimetic libraries on solid phase using a [2 -i- 3]-cycloaddition between two different Rink-amide resin-linked vinylsulfones (161) and azomethine imines. The latter were generated in situ from cyclic hydrazides (162) and various aliphatic and aromatic aldehydes (Scheme 34). The cycloaddition took place on refluxing 1,2-dichloro-ethane in a sealed tube for 48 h, followed by elimination of the p-toluenesulfonyl group with DBU. The reaction afforded a single regioisomer (164) in moderate to good yields. 

Diethyl 2-oxo-3-alkenylphosphonates, which are readily accessible from diethyl 2-oxopropylphos-phonate, are useful heterodienes in Diels-Alder reactions. Cycloaddition reactions with vinyl ethers in ( I I in a sealed tube at 85-130°C give satisfactory yields (57-88%) of dihydro-27/-pyrans. The products are isolated as a mixture of 2,4-tra .v and 2,4-czT isomers. When treated with 4 M HCl in THF, the dehydropyran hemiacetal moiety is readily hydrolyzed to provide diethyl 5-formyl-2-oxopentylphosphonates in excellent yields (72-92%, Scheme 5.59). When R> = R =H, the aldehyde undergoes smooth cyclization leading to diethyl 2-oxocyclohexenephosphonate. ... 

Cycloaddition.2 In the presence of this nickel catalyst, methylenecyclo-propanes undergo an unusual cycloaddition across carbon-carbon double bonds. Thus methylenecyclopropane (1) when heated in a sealed tube (60°, 48 hrs.) with excess methyl acrylate in the presence of bis(acrylonitrile)nickel(0) gives the 1 1 adduct, methyl 3-methylenecyclopentanecarboxylate (2), in 82% yield. Methyl vinyl ketone or acrylonitrile is also a suitable substrate. The reaction provides a useful synthesis of methylenecyclopentane derivatives. 

Diphenylcyclobutanones. Contrary to earlier reports, diphenylketene undergoes cycloaddition with simple alkenes to give 2,2-diphenylcyclobutanones.1 However, a long reaction time is needed for satisfactory yields. cw-Olefins react much faster than trans-olefins. Thus the reaction with cis-butene-2 requires 3 days, but the reaction with frans-butene-2 requires 3 months. With low-boiling alkenes, the reaction is carried out in a sealed tube or in an autoclave. 

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