Isomeric adducts

Another stereochemical feature of the Diels-Alder reaction is addressed by the Alder rule. The empirical observation is that if two isomeric adducts are possible, the one that has an unsaturated substituent(s) on the alkene oriented toward the newly formed cyclohexene double bond is the preferred product. The two alternative transition states are referred to as the endo and exo transition states ... 

It was stated that tertiary amines 304 derived from pyrrolidines [R = alkyl, benzyl, SiMcs, Si(t-Bu)2Me] add very efficiently (yields up to 94%) to (5R)-5-menthyloxy-2(5//)-furanone 170 under photosensitized conditions to give the isomeric adducts 305 and 306 (Scheme 82) (99TL3169). 

The stereochemistry of the addition of amines to acetylenic sulfones has been investigated by Truce and coworkers74. Reaction of phenyl 1-propynyl sulfone with ethylamine gives a mixture of ( )- and (Z)-isomeric adducts (equation 90)75. 

Dehydrogenated isomeric adducts were also present. 

The reaction of benzyne with furan was the first example of a Diels-Alder reaction of benzyne to be studied b. No authenticated examples of arynes are known which fail to give cyclo-adducts with furan i38>. The tetrahalogenobenzynes all form the expected adducts 103, X = F 6), Cl 57>i39)j gr 59) or i 59)). d0 other highly fluorinated arynes i40,i4i>. The isomeric adducts (104) and (105) have been detected by 19F n.m.r. spectroscopy when the dilithio-compound (12) was allowed to decompose in the presence of furan 28 103). 

Evidence for slow inversion at nitrogen in the compound (106) and its tetrachloro analogue has been obtained 142>. The adduct of tetra-fluorobenzyne with cyclopentadiene has been obtained but of rather more interest is the isolation of the isomeric adducts (108) and (109) from the reaction of tetrafluorobenzyne with nickelocene 143>. No adducts were obtained from attempted reactions with ferrocene 144 80). 

It had been reported that, for example, 5.7.9(ll)-cholestatrienyl acetate shows a greater reactivity towards dienophiles than the corresponding 5,7-dienes 153>. We therefore investigated reactions with tetra-fluoro- and tetrachloro-benzyne 152>. The two isomeric adducts (115) and (116) were obtained in only modest yields with tetrafluorobenzyne, while with tetrachlorobenzyne no adducts or ene products were isolated. 

MCP (1) is not known to undergo [4 + 2] cycloadditions. The substitution of two, or more, ring protons with fluorine atoms, however, seems to improve dramatically the dienophilic reactivity of the exocyclic double bond. 2,2-Di-fluoromethylenecyclopropane (5) is a quite reactive dienophile in Diels-Alder cycloadditions. With cyclopentadiene (6) and furan (7), it formed two isomeric adducts (Scheme 1) [9]. In both cases the adduct with the endo CF2 group is the major isomer. 

Intramolecular [n2 + 2] photocycloadditions are equally numerous and many have considerable synthetic potential. 4-(But-3-enyloxy)quinol-(l//)2-one (254), for example, is converted into a mixture of isomeric adducts 255 and 256 on irradiation in methanol.208 Intramolecular cycloaddition has also been observed in the pyrimidinedione 257209 and in the dehydrovaline acrylamide 258 which on irradiation in dioxane affords the novel /1-lactam system 259.210... 

Linders et al. [73] studied the Diels-Alder reaction of 6-demethoxy-/J-dihydrothe-baine with an excess of methyl vinyl ketone (used both as reactant and solvent), which gives a mixture of two isomeric adducts. When the reaction was performed using classical heating extensive polymerization occurred, whereas much less poly-... 

The thermal reaction of the [HB, TCNE] complex leads to a different mixture of isomeric adducts compared to those obtained by charge-transfer cycloaddition208 (equation 74). 

Pukhnarevich et al. (55) showed that the structure of silanes, R3SiH (in which R3 was 15 combinations of R = Me, Et, n-Pr, i-Pr, i-Bu, Me3SiO—, C1CH2, EtO, i-PrO, and Ph) had very little effect on the ratio of isomeric adducts that form by their addition to 1-hexyne with chlo-roplatinic acid according to Eq. (60). 

A number of addition reactions to the salt (150) have been reported.140 With azide ion, the ylide (151) is formed. Diels-Alder addition of cyclopentadiene occurs to form isomeric adducts (152). With thioamides, a mixture of the salts (153) and (154) results, and with, e.g., 2-aminopyridine, the salt (155) is formed. 

The triazolinedione adds to cycloheptatriene and cyclooctatetraene to yield the valence-isomeric adducts 265 and 266, respectively (equations 143 and 144)136. 

Strueturally related adduets include the 8-phenol derivatives, 8-(4"-hydroxyphenyl)-dG (8-p-PhOH-dG), and 8-(2"-hydroxyphenyl)-dG (8-o-PhOH-dG) that are generated by reaetion of phenol with excess nitrite.This reaetion generates diazoquinones that break down into hydroxyphenyl radicals that attach covalently to C-8 of dG. Diazoquinones are mutagenic in the Ames test without metabolie aetivation, and it is expected that hydroxyphenyl radicals and the isomeric adducts, 8-p-PhOH-dG and 8-o-PhOH-dG, play a key role in the mutagenie activity of diazoquinones. Careinogenic PAHs, such as benzo[a]pyrene (BP), also form C8-dG adducts (8-BP-dG, Fig. 7). 2,173 hile classical metabolic activation of... 

An example of a sugar-derived chiral -haloketone is offered by 24. When ulosyl bromide 24 is coupled to acetaldehyde in a Grignard-type process, a mixture of isomeric adducts is formed, where the 50% is represented by 25, possessing the (R) configuration at the hydroxy ethyl substituent (equation 21). The same protocol is applied in an efficient nucleophilic C-glycosidation reaction of 24 with galactose-derived aldehyde 26 to give 27 (equation 22)20. 

Dihydrobenzo[c]furans have been dehydrogenated directly to benzo[c]furans using / -chloranil in xylene.lo .ioe stereochemistry of the 4,5-diaroylcyclohexenes is generally not known. Sometimes two isomers have been isolated. As was reported by Adams and Geissman, the reaction of 2,4-hexadiene with dibenzoylethylene gave a major product in 66% yield (mp 136—137°C) in addition, an isomeric compound (mp 86-88 C, 5%) was isolated. Two isomeric adducts (mp 120°C, 178-179°C) have also been obtained from the reaction of 1,4-diphenylbutadiene with dibenzoylethylene. Both cis- and tra 5-dibenzoylethylene with 2,3-dimethylbutadiene gave the same stereoisomer. ... 

The adduct formation from the reaction of the 3,5-dinitropyridine with MeONa was first reported by Fyfe.13 In DMSO solution the reaction is accompanied by the disappearance of the NMR spectrum of the substrate and the appearance of three new signals of equal intensity. Furthermore, one of the three ring proton signals is much more shielded than in the substrate, due to the hybridization change from sp2 to sp3. The observed pattern is in agreement with structure 1. Subsequent NMR and spectrophotometric studies have shown that the isomeric adduct 2 competitively forms together with 1 and eventually turns into the latter, due to a substantial difference in stability.35,36,45 The conversion 2 — 1 is accelerated by methanol. The more... 

The behavior of 4-methoxy-3,5-dinitropyridine bears a substantial analogy with that of 2,4,6-trinitroanisoIe, which also yields two isomeric adducts (7 and 8) resulting from attack at the CH and COMe positions, respectively.48... 

Methoxy-5-nitropyrimidine is also attacked at a CH position, as indicated by the relatively high upheld shift of one of the ring protons.14,41 The formation of the gem-dimethoxy adduct is thus ruled out. Of the two possible isomeric adducts only the one resulting from attack at the 2-position (17) is formed, as unequivocally shown by the singlet at <5 5.75, which is observed starting from 4-methoxy-5-nitropyrimidine-6-rf.41... 

Several pyridine substrates can yield two isomeric adducts.45,46 It has often been found that one of them (AK) is kinetically favored, whereas the other (At) is thermodynamically favored. The independent rates of attainment of the equilibrium (Aeq) for the formation of AK and Ax, respectively, are expressed by Eqs. (5) and (6). The reaction scheme is illustrated by Eq. (7). 

More complex reaction patterns are observed for the reversible formation of two isomeric adducts from the same substrate (Eq. 7). In such cases the kinetic form takes into account the formation of the AK and AT species as discussed above (see Section II,B,2). Thus the interaction leads to two distinguishable processes, the first of which consists of the formation of a mixture in which AK is predominant. The related observed rate constant for this process is expressed according to Eq. (9). 

No evidence has been found for the presence of the isomeric adduct 97 in spite of the presence of a small amount of 2-phenylpyrimidine (nearly 4%) in the reaction mixture as obtained after hydrolysis of the adduct to dihydropyrimidine and subsequent oxidation. The composition of the reaction mixture is not affected if TMEDA is added. 

By the action of phenyllithium, pyridazine is converted to adduct 100 (Table XVI), resulting from nucleophilic attack at position 3.34 The structural assignment is based upon H- and 13C-NMR, starting with pyridazine and its 4,5-dideutero derivative. The site of attachment of the phenyl group is other than that observed with the amide ion in ammonia (C-4). Analysis of the products obtained after hydrolysis and oxidation indicates the presence of nearly 5-6% of 4-phenyIpyridazine. Although this finding implies the formation of a small amount of the isomeric adduct 101, there is no NMR evidence for it. However, both isomeric adducts can be detected when the reaction is carried out in the presence of TMEDA or tetrahydrofuran at a lower temperature. The chemical shift values of adduct 101 are closely similar to those of the amino analog 29. 

Similar conclusions are reached for the distribution of electron density in the isomeric adduct 101, where the carbon atoms adjacent to the reaction center are shifted upheld with respect to the corresponding 1,4-dihydropyridazine. Somewhat higher shielding is found for the C-5 atom (8.0 ppm) than for C-3 (3.7 ppm), but in either position the electron density appears to be appreciably lower than for C-4 in adduct 100. Such differences are presumably to be related to the nature of the lithium-nitrogen bond, but clearly to a hrst approximation all the adducts from diazines and phenyllithium can be described as undissociated species, whether that bond is ionized or strongly polar covalent. 

At lower temperature (-15°C) and in 7 3 (v/v) DMSO-d6-MeOD, evidence is obtained for the primary formation of the isomeric adduct 178, resulting from attack at position 5. Adduct 178 shows a signal at 3 5.48, which gradually decreases and finally disappears as the intensity of the spectrum of 177 increases. 

The testosterone ester derivative (10 mmol) is dissolved in ca. 100 ml of a solution of hydrazoic acid in chloroform (0.15 M)138 and treated with stirring with a solution of 20 ml of f-butyl alcohol and N-chlorosuccinimide (2 g, 15 mmol). The reaction mixture is stirred for 8-10 hr and then added with stirring to a saturated solution of sodium bisulfite. The mixture is diluted with 200 ml of chloroform and washed with water. The chloroform layer is further washed with dilute sodium bicarbonate solution and water, dried (Na2S04) and the solvent removed in vacuo. The residual /-butyl alcohol is removed by repeatedly adding methanol to the product and concentrating to dryness in vacuo. The residue is triturated four times with Skellysolve F to separate the two isomeric adducts, (103) and (104). 

Aminopyrazole (104) with MP and MPP gave121 the 5-oxo-4,5-dihydropyrazolo[l,5-a]pyrimidines (105 and 106), whereas with DMAD the 7-oxo-4,7-dihydro derivative (108) was formed. Both types of adduct, 107 and 109, were obtained from tetrolic ester. In acetic acid, MP and and the aminopyrazole gave 4-oxo-4,7-dihydro-l//-pyrazolo[3,4-61-pyridine (110), a compound which was also formed from 104 and /J-ethoxyacrylic ester. The aminopyrazolone 111 gave the isomeric adducts 112 and 113 with DMAD together with a 1 1 molar addition product of DMAD and 112 or 113. 

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