Functionalization diazo compounds

Two general methods are available for tbe assembly of tbe sterically stabilized species 16-24, both starting from metallic derivatives of diazo compounds (147) (16). Tbe latter have two nucleopbilic centers and can, in principle, react with electrophiles at C giving the functionalized diazo compounds (148), or at N, which... 

Rhodium(II)-mediated reactions have found many applications. The literature up to 1985 in intramolecular and intermolecular cyclopropanations, including choice of catalysts and mechanistic aspects, has been thoroughly reviewed by Maas [9]. More recent reviews are available that focus on the ligand effects and mechanism [10], and on their utilization in fine organic synthesis as well as in natural product synthesis [11]. All of these reviews, and in particular McKervey s comprehensive review [11a] on organic synthesis with a-diazocarbonyl compounds, deal with the utilization of functionalized diazo compounds as carbenoid precursors. Herrmann et al. surveyed the organometallic chemistry of diazoalkanes [11c, lid]. 

Excess diazomethane has been used to convert phenols to methyl ethers in the presence or absence of acids . Employment of transition metal derivatives, typically Rh2(OAc)4 and recently CHsReOs , allows one to react functionalized diazo compounds in an intramolecular or intermolecular 0-aUtylation (equation 13). The stability of diazo compounds derived from active methylene compounds toward OH insertion was compared... 

Pyrazoles are formed when the diazo compounds react with alkynes or with functionalized alkenes, viz. the enols of /3-diketones. Pyrazolenines (353 Section 4.04.2.2.1) are isolated from disubstituted diazomethanes. Many pyrazoles, difficult to obtain by other methods, have been prepared by this procedure, for example 3-cyanopyrazole (616) is obtained from cyanoacetylene and diazomethane (7iJCS(C)2i47), 3,4,5-tris(trifiuoromethyl)pyrazole (617) from trifluorodiazoethane and hexafluoro-2-butyne (8lAHC(28)l), and 4-phenyl-3-triflylpyrazole (618 R =H) from phenyltriflylacetylene and diazomethane (82MI40402). An excess of diazomethane causes iV-methylation of the pyrazole (618 R = H) and the two isomers (618 R = Me) and (619) are formed in a ratio of 1 1. 

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). 

Whereas the utility of these methods has been amply documented, they are limited in the structures they can provide because of their dependence on the diazoacetate functionality and its unique chemical properties. Transfer of a simple, unsubstituted methylene would allow access to a more general subset of chiral cyclopropanes. However, attempts to utilize simple diazo compounds, such as diazomethane, have never approached the high selectivities observed with the related diazoacetates (Scheme 3.2) [4]. Traditional strategies involving rhodium [3a,c], copper [ 3b, 5] and palladium have yet to provide a solution to this synthetic problem. The most promising results to date involve the use of zinc carbenoids albeit with selectivities less than those obtained using the diazoacetates. 

The strained bicyclic carbapenem framework of thienamycin is the host of three contiguous stereocenters and several heteroatoms (Scheme 1). Removal of the cysteamine side chain affixed to C-2 furnishes /J-keto ester 2 as a possible precursor. The intermolecular attack upon the keto function in 2 by a suitable thiol nucleophile could result in the formation of the natural product after dehydration of the initial tetrahedral adduct. In a most interesting and productive retrosynthetic maneuver, intermediate 2 could be traced in one step to a-diazo keto ester 4. It is important to recognize that diazo compounds, such as 4, are viable precursors to electron-deficient carbenes. In the synthetic direction, transition metal catalyzed decomposition of diazo keto ester 4 could conceivably furnish electron-deficient carbene 3 the intermediacy of 3 is expected to be brief, for it should readily insert into the proximal N-H bond to... 

The diazo function in compound 4 can be regarded as a latent carbene. Transition metal catalyzed decomposition of a diazo keto ester, such as 4, could conceivably lead to the formation of an electron-deficient carbene (see intermediate 3) which could then insert into the proximal N-H bond. If successful, this attractive transition metal induced ring closure would accomplish the formation of the targeted carbapenem bicyclic nucleus. Support for this idea came from a model study12 in which the Merck group found that rhodi-um(n) acetate is particularly well suited as a catalyst for the carbe-noid-mediated cyclization of a diazo azetidinone closely related to 4. Indeed, when a solution of intermediate 4 in either benzene or toluene is heated to 80 °C in the presence of a catalytic amount of rhodium(n) acetate (substrate catalyst, ca. 1000 1), the processes... 

Carbonyl oxides (formed by the reaction of diazo compounds with singlet oxygen) may also be used to oxidize sulphoxides74. The corresponding sulphone is formed in reasonable yields and the reaction may be carried out in the presence of the sulphide functionality. The reaction proceeds as shown in equation (21) and involves initial nucleophilic attack by the carbonyl oxide on the sulphoxide sulphur atom followed by the facile departure of the carbonyl compound yielding the required sulphone. 

Of the following amine-reactive and photoreactive crosslinkers, the overwhelming majority use an aryl azide group as the photosensitive functional group. Only a few use alternative photoreactive chemistries, particularly perfluorinated aryl azide, benzophenone, or diazo compounds. For general background information on photoreactive crosslinkers, see Das and Fox (1979), Kiehm and Ji (1977), Vanin and Ji (1981), and Brunner (1993). 

The rhodium(II)-catalyzed reaction of propargyl compounds 169 and diazo compounds 170 gave corresponding functionalized allenes 171 together with cydopro-penes 172 (Scheme 3.87) [126]. Rh2(pfb)4, where pfb represents perfluorobutyrate, was found to be an excellent catalyst for preparing the allenes 171. An analogous rhodium(II) complex, Rh2(OAc)4, afforded mainly 172 with only a trace amount of 171 (<5%). 

Principally the same, but chemically simpler, sequence was used to prepare arylnitro anion-radicals from arylamines, in high yields. For instance, aqueous sodium nitrite solution was added to a mixture of ascorbic acid and sodium 3,5-dibromo-4-aminobenzenesulfonate in water. After addition of aqueous sodium hydroxide solution, the cation-radical of sodium 3,5-dibromo-4-nitro-benzenesulfonate was formed in the solution. The latter was completely characterized by its ESR spectrum. Double functions of the nitrite and ascorbic acid in the reaction should be underlined. Nitrite takes part in diazotization of the starting amine and trapping of the phenyl a-radical formed after one-electron reduction of the intermediary diazo compound. Ascorbic acid produces acidity to the reaction solution (needed for diazotization) and plays the role of a reductant when the medium becomes alkaline. The method described was proposed for ESR analytical determination of nitrite ions in water solutions (Lagercrantz 1998). 

Non-functionalized aliphatic diazo compounds are fairly rare, and so are their reductions. Good examples of the reduction of diazo compounds to either amines or hydrazones are found with a-diazo ketones and a-diazo esters (pp. 124, 125, 160). 

In 2007, Maruoka et al. introduced chiral dicarboxylic acids consisting of two carboxylic acid functionalities and an axially chiral binaphthyl moiety. They applied this new class of chiral Brpnsted acid catalyst to the asymmetric alkylation of diazo compounds withA-Boc imines [91]. The preparation of the dicarboxylic acid catalysts bearing aryl groups at the 3,3 -positions of the binaphthyl scaffold follows a synthetic route, which has been developed earlier in the Maruoka laboratory [92]. 

In search of a convenient procedure for preparing diazo substrates for the cycloaddition to Cgg, Wudl introduced the base-induced decomposition of tosyl-hydrazones [116]. This procedure allows the in situ generation of the diazo compoimd without the requirement of its purification prior to addition to Cgg. Since they are rapidly trapped by the fullerene, even unstable diazo compounds can be successfully used in the 1,3-dipolar cycloaddition. In a one-pot reaction the tosyUiydrazone is converted into its anion with bases such as sodium methoxide or butylHfhium, which after decomposition readily adds to Cgg (at about 70 °C). This method was first proven to be successful with substrate 142. Some more reactions that indicate the versatility of this procedure are shown in Table 4.4. Reaction of 142 with CgQ under the previously described conditions and subsequent deprotection of the tert-butyl ester leads to [6,6]-phenyl-C5j-butyric acid (PCBA) that can easily be functionalized by esterification or amide-formation [116]. PCBA was used to obtain the already described binaphthyl-dimer (obtained from 149 by twofold addition) in a DCC-coupling reaction [122]. 

Due to space limitations, it is not possible to provide a comprehensive coverage of all 1,3-dipolar cycloaddition chemistry carried out using diazo compounds over the past two decades. Rather, attention will be given to the most significant developments, including the synthesis of novel heterocyclic systems, the preparation of well-established heterocycles (such as pyrazoles and pyrazolines) with novel functionalities, as well as stereoselective cycloadditions. A discussion of the theoretical, mechanistic, and kinetic aspects of these 1,3-dipolar cycloaddition reactions will be kept to a minimum, but references to important work in these areas will be given at appropriate places. Authoritative reviews dealing with the... 

Other novel diazo compounds that have been subjected to 1,3-dipolar cycloaddition with activated alkenes, and that give unusually functionalized pyrazolines (Scheme 8.7), include l-diazo-3-trimethylsilylpropan-2-one (20) (49), 2-diazo-methyl-4(57/)-furanones (21) (50), methyl 2-diazo-5-methylanilino-5-oxopentano-ate (22) (51), 2-(acylamino)-2-diazoacetates (23) (51), ethyl 2-diazo-4,4,4-trichloro-3-(ethoxycarbonylamino)butyrate (24) (52), and diazopropyne (53). 

Carrie and co-workers studied the cycloaddition of oxime esters derived from methyl cyanoacetate and malonate esters 82 (Scheme 8.20) with diazomethane and some monosubstituted derivatives. Thermally labile 1,2,3-triazolines 83 were obtained when tosyloxy- and benzoyloxyimines were used (141), while methyl acetoxyimino-cyanoacetate (82, X = CN, Y = C02Me, = Ac) gave products derived from both a 1,2,3- and a 1,2,4-triazoline, depending on the stmcture of the diazo compound (142). Not unexpectedly, diazomethane reacted with the corresponding imino-malononitrile (82, X = Y = CN) system at the nitrile function rather than at the C=N bond (143). 

When phosphaalkynes are exposed to bis- and tris(diazo) compounds, bis- or tris(l,2,4-diazaphosphol-5-yl) compounds are formed that may be further converted into a variety of novel heterocyclic systems. For example, bis- and tris[diazo(tri-methylsilyl)methyl]phosphanes 237 and 240 afforded bis- and tris(diazaphospho-lyl)phosphanes 238 and 241 after cycloaddition with terf-butylphosphaacetylene followed by a subsequent 1,5-silyl shift (Scheme 8.56) (300). Reaction with electrophilic halides at the Wsilyl functions allows the introduction of a heteroatom bridge between the diazaphosphole ring leading to polycyclic ring systems such as 239 and 242. 

Moreover, each of the four ortho carbons is also protected from the approach of external reagents by these bromine groups. This stabilization enabled us to introduce connecting groups at the para position of the monomer diazo compound (e.g., 119) to give the functionalized monomer 120, and then to connect it to an appropriate linker satisfying the topological requirement for intramolecular... 

Becker, AnalChem 22, 185-88(1950) CA 44, 3407 (1950) (Detn of N-contg functional groups in org compds) 9) O. Siis et al, Ann 598, 123-38(1956) CA 51, 321-23(1957) (Light-induced degradation products of diazo derivs) 10) LA. D yakonov, "Alifatiches-kie Diazosoedineniya (Aliphatic Diazo Compounds), Izdatel , Leningrad, Moscow(1958), 138 pp... 

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