Diazo compounds substituents

The problem of the synthesis of highly substituted olefins from ketones according to this principle was solved by D.H.R. Barton. The ketones are first connected to azines by hydrazine and secondly treated with hydrogen sulfide to yield 1,3,4-thiadiazolidines. In this heterocycle the substituents of the prospective olefin are too far from each other to produce problems. Mild oxidation of the hydrazine nitrogens produces d -l,3,4-thiadiazolines. The decisive step of carbon-carbon bond formation is achieved in a thermal reaction a nitrogen molecule is cleaved off and the biradical formed recombines immediately since its two reactive centers are hold together by the sulfur atom. The thiirane (episulfide) can be finally desulfurized by phosphines or phosphites, and the desired olefin is formed. With very large substituents the 1,3,4-thiadiazolidines do not form with hydrazine. In such cases, however, direct thiadiazoline formation from thiones and diazo compounds is often possible, or a thermal reaction between alkylideneazinophosphoranes and thiones may be successful (D.H.R. Barton, 1972, 1974, 1975). 

Diazo compounds react with alkenes to afford A -pyrazolines, which in turn izomerize to A -pyrazolines if there is a hydrogen atom a to the N=N bond (Scheme 54). In those cases where two possible ways of isomerization exist, the more acidic hydrogen migrates preferentially. The alkene configuration is conserved on the A -pyrazoline (stereospecificity) but the regioselectivity depends on the substituents of both the alkene and the diazo compound. 

Sheremetev and co-workers employed diazo compounds of type 60, prepared from the corresponding amines in moderate yields as alternative excellent precursors for the preparation of side-chain-functionalized derivatives (Scheme 29). Several furazans bearing reactive groups or cyclopropyl or five-membered heterocyclic substituents have been prepared by standard procedures (99MI6). 

Instead of a diazonium salt, a diazo compound is obtained from reaction of a primary aliphatic amine 8 that has an electron-withdrawing substituent at the a-carbon (e.g. Z = COOR, CN, CHO, COR) as well as an a-hydrogen ... 

Such diazo compounds 3 however, that contain two electron-withdrawing substituents, are unstable under these reaction conditions. They further react by hydrolytic cleavage of one carbonyl substituent to give an anionic species 6, that is stabilized by resonance, and which yields the hydrazone 4 upon acidic workup ... 

The synthesis of thiepins 14 was unsuccessful in the case of R1 = i-Pr,79 but if the substituents in the ortho positions to sulfur arc /erf-butyl, then thiepin 14 (R1 = t-Bu R2 = Me) can be isolated in 99% yield.80 Rearrangement of diazo compound 13 (R1 = t-Bu R2 = H), which does not contain the methyl group in position 4, catalyzed by dimeric ( y3-allyl)chloropalladium gives, however, the corresponding e.w-methylene compound. The thiepin 14 (R1 = t-Bu, R2 = H) can be obtained in low yield (13 %) by treatment of the diazo compound with anhydrous hydrogen chloride in diethyl ether at — 20 C.13 In contrast, the ethyl thiepin-3,5-or -4,5-dicarboxylates can be prepared by the palladium catalysis method in satisfying yields.81... 

Testing for excess of nitrous acid at the end of the reaction. For this purpose starch-potassium iodide papers are best used, and these indicate nitrite in acid solution by turning blue instantaneously. With some practice, the nitrite reaction can be clearly distinguished from the coloration caused by certain diazo compounds, such as those bearing nitro substituents. The latter react only after 0.5 to 2 seconds. Often the difference becomes more marked after dilution of the diazo solution with concentrated hydrochloric acid. A properly conducted diazotization should exhibit on completion a very weak nitrite reaction, corresponding to an excess of about 10 4 m. 

Much earlier information on the structure of diazonium ions than that derived from X-ray analyses (but still useful today) was obtained by infrared spectroscopy. The pioneers in the application of this technique to diazonium and diazo compounds were Le Fevre and his school, who provided the first IR evidence for the triple bonds by identifying the characteristic stretching vibration band at 2260 cm-1 (Aroney et al., 1955 see also Whetsel et al., 1956). Its frequency lies between the Raman frequency of dinitrogen (2330 cm-1, Schrotter, 1970) and the stretching vibration frequency of the C = N group in benzonitrile (2255 cm-1, Aroney et al., 1955). In substituted benzenediazonium salts the frequency of the NN stretching vibration follows Hammett op relationships. Electron donor substituents reduce the frequency, whereas acceptor substituents increase it. The 4-dimethylamino group, for example, shifts it by 103 cm-1 to 2177 cm-1 (Nuttall et al., 1961). This result supports the hypothesis that... 

Carbenes from Diazo Compounds. Decomposition of diazo compounds to form carbenes is a quite general reaction that is applicable to diazomethane and other diazoalkanes, diazoalkenes, and diazo compounds with aryl and acyl substituents. The main restrictions on this method are the limitations on synthesis and limited stability of the diazo compounds. The smaller diazoalkanes are toxic and potentially explosive, and they are usually prepared immediately before use. The most general synthetic routes involve base-catalyzed decomposition of V-nitroso derivatives of amides, ureas, or sulfonamides, as illustrated by several reactions used for the preparation of diazomethane. 

Diazo compounds can also be obtained by oxidation of the corresponding hydrazone,129 the route that is most common when one of the substituents is an aromatic ring. 

The study on 2,7-di-rerf-butylthiepin has recently been extended to explore more simply substituted thiepins 58). The palladium-catalyzed reaction of the diazo compound 107 lacking a 4-methyl substituent gives exclusively the exo-methylene compound 108 whereas the acid-catalyzed reaction of the same precursor 107 resulted in the formation of 2,7-di-/er/-butyl-4-ethoxycarbonylthiepin (109)58). Due to the substantial thermal stability of 109 it is possible to transform the ethoxy-carbonyl group into the hydroxymethyl (110), trimethylsilyloxymethyl (111) and formyl group (112)58). 

For many catalytic cyclopropanations, the stereoselectivity describing the stereochemical relation between substituents at the carbenoid and those at the double bond is not very pronounced. EjZ or syn/anti ratios of ca. 1-3 in favor of the less congested isomer may be considered normal (for examples see Tables 6 and 7). The stereochemical outcome can be expected to be governed by the nature of the olefin, the diazo compound and the catalyst. 

Enantioselective carbenoid cyclopropanation can be expected to occur when either an olefin bearing a chiral substituent, or such a diazo compound or a chiral catalyst is present. Only the latter alternative has been widely applied in practice. All efficient chiral catalysts which are known at present are copper or cobalt(II) chelates, whereas palladium complexes 86) proved to be uneflective. The carbenoid reactions between alkyl diazoacetates and styrene or 1,1 -diphenylethylene (Scheme 27) are usually chosen to test the efficiency of a chiral catalyst. As will be seen in the following, the extent to which optical induction is brought about by enantioselection either at a prochiral olefin or at a prochiral carbenoid center, varies widely with the chiral catalyst used. 

Reaction of ketocarbenoids with pyrrole and N-alkylpyrroles yields the product of formal insertion into the a-C—H bond (256) in many cases the -insertion product 257 is formed concomitantly, but generally in lower yield 238-241 >. The regioselectivity varies according to the catalyst, the diazo compound and the N-alkyl substituent. Some examples concerning the former two variables are given in Table 18 239 240). 

Interaction of an electrophilic carbene or carbenoid with R—S—R compounds often results in the formation of sulfonium ylides. If the carbene substituents are suited to effectively stabilize a negative charge, these ylides are likely to be isolable otherwiese, their intermediary occurence may become evident from products of further transformation. Ando 152 b) has given an informative review on sulfonium ylide chemistry, including their formation by photochemical or copper-catalyzed decomposition of diazocarbonyl compounds. More recent examples, including the generation and reactions of ylides obtained by metal-catalyzed decomposition of diazo compounds in the presence of thiophenes (Sect. 4.2), allyl sulfides and allyl dithioketals (Sect. 2.3.4) have already been presented. 

It was demonstrated (83) that the reaction of dinitrostyrenes (28) with aryl diazo compounds RR CN2 afford nitronates (24 g) in good yields. These products contain the nitro group at the C-4 atom in the trans position with respect to the substituent at C-5 (if R =H). Since the reaction mechanism remains unknown, the direct formation of cyclic nitronates (24 g) from pyrazolines A without the intermediate formation of cyclopropanes also cannot be ruled out. 

Of course, bulky substituents kinetically stabilize carbenes, but interestingly, during the course of our study, we realized that the stability of carbenes is often inversely proportional to the stability of the starting diazo compounds,27 as illustrated in Table I. 

The reaction of (trialkylsilyl)vinylketenes with nucleophilic carbenoid reagents, such as sulfur ylides and diazo compounds, has been used for synthesis of substituted cyclopentenones by stereoselective 4 + 1-annulation (Scheme 12). The strategy relies on the remarkable ability of silyl substituents to stabilize ketenes and suppress their tendency to undergo dimerization and 2 - - 2-cycloaddition. 

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